NMDA Receptor Antagonists for Neuroprotection

ABSTRACT

Provided are compounds, pharmaceutical compositions and methods of treatment or prophylaxis of disorders associated with NMDA receptor activity, including neuropathic pain, stroke, traumatic brain injury, epilepsy, and related neurologic events or neurodegeneration. Compounds are of the general Formula I, or a pharmaceutically acceptable salt, ester, prodrug or derivative thereof are provided: 
     
       
         
         
             
             
         
       
     
     wherein:
     each (L) k -Ar 1  is a substituted or unsubstituted, mono or bicyclic aryl or heteroaryl; W is a bond, alkyl, or alkenyl; X is a bond, NR 1  or O and each R 1  and R 2  is independently H, alkyl, alkenyl or aralkyl or R 1  and R 2  taken together form a 5-8 membered ring; R 3 -R 6  are selected from certain specific substituents or a carbonyl; Y is a bond, O, S, SO, SO 2 , CH 2 , NH, N(alkyl), or NHC(═O); and Z is OH, NR 6 R 7 , NR 8 SO 2 (alkyl), NR 8 C(O)NR 6 R 7 , NR 8 C(O)O(alkyl), NR 8 -dihydrothiazole, or NR 8 -dihydroimidazole or wherein Z can fuse with Ar 2  to form selected heterocycles.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Application No.60/947,276, filed Jun. 29, 2007; U.S. Provisional Application No.60/949,120, filed Jul. 11, 2007; U.S. Provisional Application No.60/985,082, filed Nov. 2, 2007; and U.S. Provisional Application No.61/127,105, filed May 9, 2008.

FIELD OF THE INVENTION

The present invention is in the area of NMDA receptor blockers,including pH-sensitive NMDA receptor blockers, as neuroprotective drugs,and includes methods and compositions for the treatment ofneurodegeneration resulting from NMDA-receptor activation.

BACKGROUND OF THE INVENTION

The NMDA subtype of glutamate-gated ion channels mediates excitatorysynaptic transmission between neurons in the central nervous system(Dingledine et al. (1999), Pharmacological Reviews 51:7-61). Animalmodels of stroke and brain trauma confirm that glutamate released fromaffected neurons can overstimulate N-methyl-D-aspartate (NMDA)receptors, which in turn causes neuronal death. Therefore, compoundsthat block NMDA receptors have been considered candidates for treatmentof stroke and head injuries. NMDA receptors are composed of NR1, NR2 (A,B, C, and D), and NR3 (A and B) subunits, which determine the functionalproperties of native NMDA receptors. Expression of the NR1 subunit alonedoes not produce a functional receptor. Co-expression of one or more NR2subunits is required to form functional channels. In addition toglutamate, the NMDA receptor requires the binding of a co-agonist,glycine, to allow the receptor to function. A glycine binding site isfound on the NR1 and NR3 subunits, whereas the glutamate binding site isfound on NR2 subunits. At resting membrane potentials, NMDA receptorsare largely inactive due to a voltage-dependent block of the channelpore by magnesium ions. Depolarization releases this channel block andpermits passage of calcium as well as other ions.

The NMDA receptor is modulated by a number of endogenous and exogenouscompounds including, sodium, potassium and calcium ions that can notonly pass through the NMDA receptor channel but also modulate theactivity of receptors. Zinc blocks the channel through NR2A- andNR2B-containing receptors noncompetitive and voltage-independent manner.Polyamines can also either potentiate or inhibit glutamate-mediatedresponses.

Stroke is the third leading cause of death in the United States and themost common cause of adult disability. In an ischemic stroke, which isthe cause of approximately 80% of strokes, a blood vessel becomesoccluded and the blood supply to part of the brain is blocked. Ischemicstroke is commonly divided into thrombotic stroke, embolic stroke,systemic hypoperfusion (Watershed or Border Zone stroke), or venousthrombosis. NMDA antagonists have been studied as neuroprotective agentsfor acute stroke. However, these agents, including Dextrorphan, Selfoteland aptiganel HCl (Cerestat) all showed certain toxicity profiles thatrequired halting trials of these agents. Early clinical studies suggestthat psychomimetic side effects occur less frequently with glycine siteNMDA antagonists, however clinical studies have not supported aprotective role for these agents(http://www.emedicine.com/neuro/topic488.htm, Lutsep & Clark“Neuroprotective Agents in Stroke”, Apr. 30, 2004).

Epilepsy has also long been considered a potential therapeutic targetfor glutamate receptor antagonists. NMDA receptor antagonists are knownto be anti-convulsant in many experimental models of epilepsy (Bradford(1995) Progress in Neurobiology 47:477-511; McNamara, J. O. (2001) Drugseffective in the therapy of the epilepsies. In Goodman & Gliman's: Thepharmacological basis of therapeutics [Eds. J. G. Hardman and L. E.Limbird] McGraw Hill, New York).

NMDA receptor antagonists may also be beneficial in the treatment ofchronic pain. Chronic pain, including neuropathic pain such as that dueto injury of peripheral or central nerves, has often proved verydifficult to treat. Treatment of chronic pain with ketamine andamantadine has proven beneficial, and it is believed that the analgesiceffects of ketamine and amantadine are mediated by block of NMDAreceptors. Several case reports have indicated that systemicadministration of amantadine or ketamine substantially reduces theintensity of trauma-induced neuropathic pain. Small-scale double blind,randomized clinical trials corroborated that amantadine couldsignificantly reduce neuropathic pain in cancer patients (Pud et al.(1998), Pain 75:349-354) and ketamine could reduce pain in patients withperipheral nerve injury (Felsby et al. (1996), Pain 64:283-291),peripheral vascular disease (Perrson et al. (1998), Acta AnaesthesiolScand 42:750-758), or kidney donors (Stubhaug et al. (1997), ActaAnaesthesiol Scand 41:1124-1132). “Wind-up pain” produced by repeatedpinpricking was also dramatically reduced. These findings suggest thatcentral sensitization caused by nociceptive inputs can be prevented byadministration of NMDA receptor antagonists.

NMDA receptor antagonists can also be beneficial in the treatment ofParkinson's Disease (Blandini and Greenamyre (1998), Fundam ClinPharmacol 12:4-12). The anti-Parkinsonian drug, amantadine, is an NMDAreceptor channel blocker (Blanpied et al. (1997), J Neurophys77:309-323). In a small clinical trial, Amantadine reduced the severityof dyskinesias by 60% without reducing the antiparkinsonian effect ofL-DOPA (Verhagen Metman et al. (1998), Neurology 50:1323-1326).Likewise, another NMDA receptor antagonist, CP-101,606, potentiated therelief of Parkinson's symptoms by L-DOPA in a monkey model(Steece-Collier et al., (2000) Exper. Neurol., 163:239-243).

NMDA receptor antagonists may in addition be beneficial in the treatmentof brain cancers. Rapidly-growing brain gliomas can kill adjacentneurons by secreting glutamate and overactivating NMDA receptors suchthat the dying neurons make room for the growing tumor, and may releasecellular components that stimulate tumor growth. Studies show NMDAreceptor antagonists can reduce the rate of tumor growth in vivo as wellas in some in vitro models (Takano, T., et al. (2001), Nature Medicine7:1010-1015; Rothstein, J. D. and Bren, H. (2001) Nature Medicine7:994-995; Rzeski, W., et al. (2001), Proc. Nat'l Acad. Sci. 98:6372).

While NMDA-receptor antagonists might be useful to treat a number ofvery challenging disorders, to date, dose-limiting side effects haveprevented clinical use of NMDA receptor antagonists for theseconditions. Thus, despite the tremendous potential for glutamateantagonists to treat many serious diseases, the severity of the sideeffects have caused many to abandon hope that a well-tolerated NMDAreceptor antagonist could be developed (Hoyte L. et al (2004) “The Riseand Fall of NMDA Antagonists for Ischemic Stroke Current MolecularMedicine” 4(2): 131-136; Muir, K. W. and Lees, K. R. (1995) Stroke26:503-513; Herrling, P. L., ed. (1997) “Excitatory amino acid clinicalresults with antagonists” Academic Press; Parsons et al. (1998) DrugNews Perspective II: 523 569).

pH Sensitive NMDA Receptors

Two of the most prevalent subtypes of NMDA receptors (including the NR2Aand NR2B subunits or an alternatively spliced NR1 subunit) have theunusual property of being normally inhibited by protons by about 50% atphysiological pH (Traynelis, S. F. and Cull-Candy, S. G. (1990) Nature345:347; Traynelis et al. (1995) Science 268: 873-876; Traynelis et al.(1998), J Neurosci 18:6163-6175).

The extracellular pH is highly dynamic in mammalian brain, andinfluences the function of a multitude of biochemical processes andproteins, including glutamate receptor function. The pH-sensitivity ofthe NMDA receptor has received increasing attention for at least tworeasons. First, the IC₅₀ value for proton inhibition of pH 7.4 placesthe receptor under tonic inhibition at physiological pH. Second, pHchanges are extensively documented in the central nervous system duringsynaptic transmission, glutamate receptor activation, glutamate receptoruptake, and prominently during pathological states such as ischemia andseizures (Siesjo, B K (1985), Progr Brain Res 63:121-154; Chesler, M(1990), Prog Neurobiol 34:401-427; Chesler and Kaila (1992), TrendsNeurosci 15:396-402; Amato et al. (1994), J Neurophysiol 72:1686-1696).

During stroke, transient ischemia leads to a dramatic drop of pH to6.4-6.5 in the core region of the infarct, with a modest drop in regionssurrounding the core. The penumbral region, which surrounds the core andextends outward, suffers significant neuronal loss. The pH in thisregion drops to around pH 6.9. The pH-induced drops are exaggerated inpresence of excess glutamate, and attenuated in hypoglycemic condition(see, for example, Mutch & Hansen (1984) J Cereb Blood Flow Metab 4:17-27, Smith et al. (1986) J Cereb Blood Flow Metab 6: 574-583;Nedergaard et al. (1991) Am J Physiol 260 (Pt3): R581-588; Katsura et al(1992a) Euro J Neursci 4: 166-176; and Katsura & Siesjo (1998) “Acidbase metabolism in ischemia” in pH and Brain function (Eds Kaila &Ransom) Wiley-Liss, New York).

In addition to ischemia, there are various other examples of conditionsin which pH changes can be associated with pathological processes,including neuropathic pain, Parkinsons disease, epilepsy and traumaticbrain injuries.

Neuropathic pain, which is due to hyperactivity of nerve fibers in thedorsal horn of the spinal chord can be associated with pH changes in thespinal cord. Single electrical stimulation of isolated spinal cord fromrat pups produces an alkaline shift of 0.05 pH units, and a 0.1 pH unitshift following 10 Hz stimulation which is followed by acidificationafter cessation of the stimuli. This acidification is greater in olderanimals (Jendelova & Sykova (1991) Glia 4: 56-63), indicating anincreased pH differential underlying the stimuli. Similarly, 30-40 Hzstimulation of the dorsal root in frog produced in vivo a transientextracellular acidification reaching a maximum ceiling of 0.25 pH unitreduction in the lower dorsal horn. Extracellular pH changes increasedwith stimulus intensity and frequency (Chvatal et al. (1988) PhysiolBohemoslov 37: 203-212). Further, high frequency (10-100 Hz) nervestimulation in adult rat spinal cord in vivo produced triphasicalkaline-acid-alkaline shifts in extracellular pH (Sykova et al. (1992)Can J Physiol Pharmacol 70: Suppl 5301-309). Additionally, it has beenshown that acute nociceptive stimuli (pinch, press, heat) applied to therat hindpaw produced transient acidification of 0.01-0.05 pH units inthe lower dorsal horn in vivo (laminae III-VII). Chemical or thermalperipheral injury produced prolonged 2 hour decreases in interstitial pHof 0.05-0.1 pH units. High frequency nerve stimulation produced analkaline pH shift followed by a dominating 0.2 pH unit acid shift(Sykova & Svoboda (1990) Brain Res 512: 181-189). Thus, increased firingof pain fibers can cause a decrease in pH (acidification) of the dorsalhorn of the spinal cord.

Subthalamic neurons are overactive in Parkinson's disease, which mayresult in a lower local pH. There is a correlation in brain regionsbetween neuronal activity and extracellular pH, with activity causingacidification. High frequency stimulation of brain slices gives aninitial acidification followed by an alkalinization, followed by a slowacidification (See, for example, Chesler (1990) Prog Neurobiol 34:401-427, Chesler & Kaila (1992) Tr Neurosci 15: 396-402, and Kaila &Chesler (1998) “Activity evoked changes in extracellular pH” in pH andBrain function (eds Kaila and Ransom). Wiley-Liss, New York).

Acidification also occurs during seizures. Electrographic seizures in awide range of preparations have been shown to cause a change inextracellular pH. For example, up to a 0.2-0.36 drop in pH can occur incat fascia dentata or rat hippocampal CA1 or dentate during anelectrically or chemically evoked seizure. Deeper drops in pHapproaching 0.5 can occur under hypoxic conditions (Siesjo et al (1985)J Cereb Blood Flow Metab 5: 47-57; Balestrino & Somjen (1988) J Physiol396: 247-266; and Xiong & Stringer (2000) J Neurophysiol 83: 3519-3524).

In addition, other types of brain injury can result in acidification.“Spreading depression” is a term used to describe a slowly moving waveof electrical inactivity that occurs following a number of traumaticinsults to brain tissue. Spreading depression can occur during aconcussion or migraine. Acidic pH changes occur with spreadingdepression. Systemic alkalosis can occur with reduction in overallcarbon dioxide content (hypocapnia) through, for example,hyperventilation. Conversely, systemic acidosis can occur with anincrease in blood carbon dioxide (hypercapnia) during respiratorydistress or conditions that impair gas exchange or lung function.Diabetic ketoacidosis and lactic acidosis represent three of the mostserious acute complications of diabetes and can result in brainacidification. Further, fetal asphyxia during parturition occurs in 25per 1000 births at term. It involves hypoxia and brain damage that issimilar but not identical to ischemia.

The acidification associated with pathological situations can partiallyinhibit NMDA receptors, which provides negative feedback that reducestheir contribution to neurotoxicity and seizure maintenance (Kaku et al.(1993), Science 260:1516-1518; Munir and McGonigle (1995), J Neurosci15:7847-7860; Vornov et al. (1996), J Neurochem 67:2379-2389; Gray etal. (1997), J Neurosurg Anesthesiol 9:180-187; O'Donnell and Bickler(1994), Stroke 25:171-177; reviewed by Tombaugh and Sapolsky (1993), JNeurochem 61:793-803; (Balestrino and Somjen (1988), J Physiol (Lond)396:247-266; Velisek et al. (1994), Exp Brain Res 101:44-52). However,the pH sensitivity of glutamate transporters increases the likelihoodthat extracellular glutamate levels will be high during a period ofacidification (Billups and Attwell (1996), Nature (Lond) 379:171-173),which enhances the opportunity for post-insult treatment of, forexample, stroke with NMDA receptor antagonists (Tombaugh and Sapolsky(1993), J Neurochem 61:793-803).

Until 1995, it was not known whether the proton-sensitive property ofthe NMDA receptor could be exploited as a target for small moleculemodulation of the receptor to develop therapeutics. Traynelis et al.(1995 Science 268:873) reported for the first time that the smallmolecule spermine could modulate NMDA receptor function through reliefof proton inhibition. Spermine, a polyamine, shifts the pKa of theproton sensor to acidic values, reducing the degree of tonic inhibitionat physiological pH, which appears as a potentiation of function(Traynelis et al. (1995), Science 268:873-876; Kumamoto, E (1996),Magnes Res 9(4):317-327).

In 1998, it was determined that the mechanism of action of thephenylethanolamine NMDA antagonists involved the proton sensor.Ifenprodil and CP-101,606 increased the sensitivity of the receptor toprotons, thereby enhancing the proton inhibition. By shifting the pKafor proton block of NMDA receptors to more alkaline values, ifenprodilbinding causes a larger fraction of receptors to be protonated atphysiological pH and, thus, inhibited. In addition, ifenprodil was foundto be more potent at lower pH (6.5) than higher pH (7.5) as tested in anin vitro model of NMDA-induced excitotoxicity in primary cultures of ratcerebral cortex (Mott et al. 1998 Nature Neuroscience 1:659). Thesecompounds have exhibited neuroprotective properties in preclinicalmodels and lack the severe side-effect liability of other types of NMDAantagonists (e.g. PCP-like psychotic symptoms and cardiovasculareffects). Other NMDA receptor-selective derivatives of ifenprodil arebeing considered for clinical development, including CP101,606 (Mennitiet al. (1997), Eur J Pharmacol 331:117-126), Ro 25-6981 (Fischer et al.(1997), J Pharmacol Exp Ther 283:1285-1292) and Ro 8-4304 (Kew et al.(1998), Br J Pharmacol 123:463-472). Unfortunately, ifenprodil andseveral of its analogs, including eliprodil and haloperidol (Lynch andGallagher (1996), J Pharmacol Exp Ther 279:154-161; Brimecombe et al.(1998), Pharmacol Exp Ther 286(2):627-634), block certain serotoninreceptors and calcium channels in addition to NMDA receptors, limitingtheir clinical usefulness (Fletcher et al. (1995), Br J Pharmacol116(7):2791-2800; McCool and Lovinger (1995), Neuropharmacology34:621-629; Barann et al. (1998), Naunyn Schmiedebergs Arch Pharmacol358:145-152).

WO 02/072542 to Emory University describes a class of pH-dependent NMDAreceptor antagonists that exhibit pH sensitivity tested in vitro usingan oocyte assay and in an experimental model of epilepsy.

WO 06/023957 to Emory University describes processes for selection of acompound which may be useful in the treatment of an ischemic injury or adisorder that lowers the pH in a manner that activates the NMDA receptorantagonist.

There remains a need for improved neuroprotective compounds and methodsfor the treatment of neuropathologies that have reduced toxicity. Inparticular there is a need for improved treatments for neuropathic pain,inflammatory pain, stroke, traumatic brain injury, global ischemia,hypoxia, spinal cord trauma, epilepsy, and other neurodegenerativediseases and disorders.

It is therefore an object of the present invention to provide newcompounds, pharmaceutical compositions and methods for the treatment ofneuropathic and neurodegenerative diseases and disorders.

SUMMARY OF THE INVENTION

NMDA receptor antagonists of Formula I, II, III, IV and V are provided,as well as compositions and methods of use of these compounds in thetreatment or prophylaxis of neuropathic pain, stroke, traumatic braininjury, epilepsy, and neurologic events or neurodegeneration resultingfrom NMDA receptor activation. In particular, the compounds describedherein are useful as neuroprotective agents. In one embodiment, thecompounds, compositions and methods are useful in the treatment ofneuropathic pain. Compounds described herein are also useful inpreventing neurodegeneration in patients with Parkinson's, Alzheimer's,Huntington's chorea, ALS, and other neurodegenerative conditions knownto the art to be responsive to treatment using NMDA receptorantagonists.

In particular embodiments, certain NMDA receptor antagonists describedherein have enhanced activity in brain tissue having lower-than-normalpH due to pathological conditions. Conditions that can alter theregional pH include hypoxia resulting from stroke, traumatic braininjury, global ischemia that may occur during cardiac surgery, hypoxiathat may occur following cessation of breathing, pre-eclampsia, spinalcord trauma, epilepsy, status epilepticus, neuropathic pain,inflammatory pain, chronic pain, vascular dementia or glioma tumors.

In one embodiment, compounds, pharmaceutical compositions and methods oftreatment or prophylaxis of neuropathic pain, stroke, traumatic braininjury, epilepsy, and other neurologic events or neurodegenerationresulting from NMDA receptor activation comprising administering acompound to a host in need thereof are provided, wherein the compoundsis of Formula I, or a pharmaceutically acceptable salt, ester, prodrugor derivative thereof:

wherein:each L is independently C₁-C₆ alkyl, C₁-C₆ alkoxy, C(═O)—(C₁-C₆)-alkyl,C₁-C₆ haloalkyl, hydroxy, fluoro, chloro, bromo, iodo, nitro, or cyano;or two L groups may be taken together with Ar¹ to form: a dioxolane ringor a cyclobutane ring;k=0, 1, 2, 3, 4 or 5;each Ar¹ and Ar² is independently aryl or heteroaryl;W is a bond, C₁-C₄ alkyl, or C₂-C₄ alkenyl;X is a bond, NR¹ or O;each R¹ and R² is independently H, C₁-C₆ alkyl, C₂-C₆ alkenyl or C₆-C₁₂aralkyl; or

R¹ and R² can be taken together to form a 5-8 membered ring;

each R³ and R⁴ is independently H, C₁-C₆ alkyl, C₁-C₆ alkoxy,C(═O)—(C₁-C₆)-alkyl, C₁-C₆ haloalkyl, hydroxy, fluoro, chloro, bromo,iodo, nitro, or cyano; or CR³R⁴ is C═O;n=1, 2, 3 or 4;each R⁵ and R⁶ is independently H, C₁-C₆ alkyl, C₁-C₆ alkoxy,C(═O)—(C₁-C₆)-alkyl, C₁-C₆ haloalkyl, hydroxy, fluoro, chloro, bromo,iodo, nitro, or cyano; or CR⁵R⁶ is C═O or C═CH₂; or wherein —NR²—(CR⁵R⁶)_(p)— can be

Y is a bond, O, S, SO, SO₂, CH₂, NH, N(C₁-C₆ alkyl), or NHC(═O);Z is OH, NR⁶R⁷, NR⁸SO₂(C₁-C₆ alkyl), NR⁸C(O)NR⁶R⁷, NR⁸C(S)NR⁶R⁷,NR⁸C(O)O(C₁-C₆ alkyl), NR⁸-dihydrothiazole, or NR⁸-dihydroimidazole;wherein each R⁶, R⁷ and R⁸ is independently H, C₁-C₆ alkyl or C₆-C₁₂aralkyl; or

wherein R⁹ and R¹⁰ are each independently H, C₁-C₆ alkyl, aralkyl.

In certain embodiments, it has been found that certain arylsubstitutions enhance activity and safety of tri-cyclic substitutedamine NMDA receptor antagonist compounds by decreasing secondary effectssuch as hERG binding and al adrenergic receptor activation. Thus, incertain embodiments, compounds, pharmaceutical compositions and methodsof treatment or prophylaxis of neuropathic pain, stroke, traumatic braininjury, epilepsy, and other neurologic events or neurodegenerationresulting from NMDA receptor activation are provided comprisingadministering a compound to a host in need thereof are provided, whereinthe compound is of Formula V, or a pharmaceutically acceptable salt,ester, prodrug or derivative thereof:

Ar′—W′—B′—W″—Y′—Ar″—Z′  Formula V

wherein B′ is selected from the group consisting of:

W′ is a bond or C₁-C₄ alkyl;W″ is C₁-C₄ alkyl, C₁-C₄ hydroxyalkyl, C₁-C₄ haloalkyl or C(═O)—C₁-C₄alkyl;Y′ is selected from a bond, O, S, CH₂ and N;Ar′ is an substituted or unsubstituted aromatic or nonaromaticcycloalkyl which optionally may include 0-3 heteroatoms;Ar″ is an aromatic or nonaromatic cycloalkyl which optionally mayinclude 0-3 heteroatoms;Z′ is NRC(O)NR₂ wherein each R is independently selected from H, C₁-C₆alkyl or C₆-C₁₂ aralkyl; orAr″—Z′ are taken together and selected from the group consisting

In one embodiment, Ar′ is substituted by (L′)_(k′) wherein each L′ isindependently C₁-C₆ alkyl, C₁-C₆ alkoxy, C(═O)—(C₁-C₆)-alkyl, C₁-C₆haloalkyl, alkaryl, hydroxy, —O-alkyl, —O-aryl, —SH, —S-alkyl, —S-aryl,fluoro, chloro, bromo, iodo, nitro, or cyano; or two L′ groups may betaken together with Ar′ to form a dioxolane ring or a cyclobutane ring;and k′=1, 2, 3, 4 or 5.

In certain embodiments, the compounds are used for the treatment ofneuropathic pain, stroke, traumatic brain injury, epilepsy, otherneurologic events or neurodegeneration resulting from NMDA receptoractivation, Parkinson's disease, Alzheimer's disease, Huntington'schorea, ALS, and other neurodegenerative conditions known to the art tobe responsive to treatment using NMDA receptor blockers. In particularembodiments, the compounds are used for the prophylaxis of neuropathicpain, stroke, traumatic brain injury, epilepsy, other neurologic eventsor neurodegeneration resulting from NMDA receptor activation,Parkinson's disease, Alzheimer's disease, Huntington's chorea, ALS, andother neurodegenerative conditions known to the art to be responsive totreatment using NMDA receptor blockers. The compounds can beadministered on a prophylactic basis to a patient at risk of a disorderassociated with NMDA receptor overactivation, and in particular adisorder associated with a reduced pH. In particular embodiments, thecompounds act as neuroprotective agents.

In certain embodiments, the compounds are administered to a host in needthereof. In certain other embodiments, the compounds are administered incombination or alternation with other compounds that are useful in thetreatment or prophylaxis of other neurologic events or neurodegenerationresulting from NMDA receptor activation, Parkinson's disease,Alzheimer's disease, Huntington's chorea, ALS, and otherneurodegenerative conditions known to the art to be responsive totreatment using NMDA receptor blockers.

DETAILED DESCRIPTION OF THE INVENTION

It has been discovered that certain NMDA receptor antagonists are usefulin the treatment or prophylaxis of neuropathic pain, stroke, traumaticbrain injury, epilepsy, and other neurologic events or neurodegenerationresulting from NMDA receptor activation as well as Parkinson's disease,Alzheimer's disease, Huntington's chorea, ALS, and otherneurodegenerative conditions known in the art to be responsive totreatment using NMDA receptor blockers. In particular, compoundsdescribed below are useful as neuroprotective agents. In one specificembodiment, the compounds, compositions and methods are useful in thetreatment of neuropathic pain. In certain embodiments, the compoundsprovided herein are allosteric NMDA inhibitors.

In one embodiment, the IC₅₀ value of the compound is 0.01 to 10 μM, 0.01to 9 μM, 0.01 to 8 μM, 0.01 to 7 μM, 0.01 to 6 μM, 0.01 to 5 μM, 0.01 to4 μM, 0.01 to 3 μM, 0.01 to 2 μM, 0.01 to 1 μM, 0.05 to 7 μM, 0.05 to 6μM, 0.05 to 5 μM, 0.05 to 4 μM, 0.05 to 3 μM, 0.05 to 2 μM, 0.05 to 1μM, 0.05 to 0.5 μM, 0.1 to 7 μM, 0.1 to 6 μM, 0.1 to 5 μM, 0.1 to 4 μM,0.1 to 3 μM, 0.1 to 2 μM, 0.1 to 1 μM, 0.1 to 0.5 μM, 0.1 to 0.4 μM, 0.1to 0.3 μM, or 0.1 to 0.2 μM.

Certain NMDA receptor antagonists described herein have enhancedactivity in tissue having lower-than-normal pH. The acidic environmentgenerated by ischemic tissue during stroke or by other disorders isharnessed as a switch to activate the neuroprotective agents describedherein. In this way side effects are minimized in unaffected tissuesince drug at these sites are less active.

In particular embodiments, the compound is pH sensitive. In specificembodiments, the compound exhibits a potency boost of at least 2, atleast 3, at least 4, at least 5, at least 6, at least 7, at least 8, atleast 9, at least 10, at least 15 or at least 20 when comparing the IC₅₀at physiological pH versus the IC₅₀ diseased pH (i.e., (IC₅₀ at physpH/IC₅₀ at Dis pH)). In certain embodiments, the compound exhibits atleast a 30%, 35%, 40%, 45%, 50%, 55%, or 60% decrease in infarct volumewhen a patient is suffering from a stroke or related condition.

In one embodiment, the compound has an IC₅₀ value of less than 10 μM ata pH of about 6 to about 9. In one embodiment, the compound has an IC₅₀value of less than 10 μM at a pH of about 6.9. In another embodiment,the compound has an IC₅₀ value of less than 10 μM at a pH of about 7.6.In one embodiment, the compound has an IC₅₀ value of less than 10 μM atphysiological pH. In one embodiment, the compound has an IC₅₀ value ofless than 10 μM at diseased pH.

In one embodiment, the IC₅₀ value of the compound at pH 6.9 is 0.01 to10 μM, 0.01 to 9 μM, 0.01 to 8 μM, 0.01 to 7 μM, 0.01 to 6 μM, 0.01 to 5μM, 0.01 to 4 μM, 0.01 to 3 μM, 0.01 to 2 μM, 0.01 to 1 μM, 0.05 to 7μM, 0.05 to 6 μM, 0.05 to 5 μM, 0.05 to 4 μM, 0.05 to 3 μM, 0.05 to 2μM, 0.05 to 1 μM, 0.05 to 0.5 μM, 0.1 to 7 μM, 0.1 to 6 μM, 0.1 to 5 μM,0.1 to 4 μM, 0.1 to 3 μM, 0.1 to 2 μM, 0.1 to 1 μM, 0.1 to 0.5 μM, 0.1to 0.4 μM, 0.1 to 0.3 μM, or 0.1 to 0.2 μM, and the ratio of the IC₅₀values at pH 7.6 to pH 6.9 for the compound is greater than 1, 2, 3, 4,5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 40, 50, 60, 70, 80, 90, or 100.

In one embodiment, the IC₅₀ value of the compound at pH 6.9 is 0.01 to10 μM, 0.01 to 9 μM, 0.01 to 8 μM, 0.01 to 7 μM, 0.01 to 6 μM, 0.01 to 5μM, 0.01 to 4 μM, 0.01 to 3 μM, 0.01 to 2 μM, 0.01 to 1 μM, 0.05 to 7μM, 0.05 to 6 μM, 0.05 to 5 μM, 0.05 to 4 μM, 0.05 to 3 μM, 0.05 to 2μM, 0.05 to 1 μM, 0.05 to 0.5 μM, 0.1 to 7 μM, 0.1 to 6 μM, 0.1 to 5 μM,0.1 to 4 μM, 0.1 to 3 μM, 0.1 to 2 μM, 0.1 to 1 μM, 0.1 to 0.5 μM, 0.1to 0.4 μM, 0.1 to 0.3 μM, or 0.1 to 0.2 μM, and the ratio of the IC₅₀values at pH 7.6 to pH 6.9 for the compound is between 1 and 100, 2 and100, 3 and 100, 4 and 100, 5 and 100, 6 and 100, 7 and 100, 8 and 100, 9and 100, 10 and 100, 15 and 100, 20 and 100, 25 and 100, 30 and 100, 40and 100, 50 and 100, 60 and 100, 70 and 100, 80 and 100, or 90 and 100.

In other embodiments, the IC₅₀ value of the compound at pH about 7.6 is0.01 to 10 μM, 0.01 to 9 04, 0.01 to 8 μM, 0.01 to 7 μM, 0.01 to 6 μM,0.01 to 5 μM, 0.01 to 4 μM, 0.01 to 3 μM, 0.01 to 2 μM, 0.01 to 1 μM,0.05 to 7 μM, 0.05 to 6 μM, 0.05 to 5 μM, 0.05 to 4 μM, 0.05 to 3 μM,0.05 to 2 μM, 0.05 to 1 μM, 0.05 to 0.5 μM, 0.1 to 7 μM, 0.1 to 6 μM,0.1 to 5 μM, 0.1 to 4 μM, 0.1 to 3 μM, 0.1 to 2 μM, 0.1 to 1 μM, 0.1 to0.5 μM, 0.1 to 0.4 μM, 0.1 to 0.3 μM, or 0.1 to 0.2 μM, In certain ofthese embodiments, the compound exhibits a ratio of the IC₅₀ values atpH 7.6 to pH 6.9 between 1 and 100, 2 and 100, 3 and 100, 4 and 100, 5and 100, 6 and 100, 7 and 100, 8 and 100, 9 and 100, 10 and 100, 15 and100, 20 and 100, 25 and 100, 30 and 100, 40 and 100, 50 and 100, 60 and100, 70 and 100, 80 and 100, or 90 and 100. In certain otherembodiments, the compound exhibits a ratio below 10, or below 5, or 4,3, 2 or 1.

Compounds Formula I

In one embodiment, compounds, pharmaceutical compositions and methods oftreatment or prophylaxis of neuropathic pain, stroke, traumatic braininjury, epilepsy, and other neurologic events or neurodegenerationresulting from NMDA receptor activation, comprising administering to ahost in need thereof a compound of Formula I, or a pharmaceuticallyacceptable salt, ester, prodrug or derivative thereof are provided:

wherein:each L is independently C₁-C₆ alkyl, C₁-C₆ alkoxy, C(═O)—(C₁-C₆)-alkyl,C₁-C₆ haloalkyl, alkaryl, hydroxy, —O-alkyl, —O-aryl, —SH, —S-alkyl,—S-aryl, fluoro, chloro, bromo, iodo, nitro, or cyano; or two L groupsmay be taken together with Ar¹ to form: a dioxolane ring or acyclobutane ring;k=0, 1, 2, 3, 4 or 5;each Ar¹ and Ar² is independently aryl or heteroaryl;W is a bond, C₁-C₄ alkyl, or C₂-C₄ alkenyl;X is a bond, NR¹ or O;each R¹ and R² is independently H, C₁-C₆ alkyl, C₂-C₆ alkenyl or C₆-C₁₂aralkyl; or

R¹ and R² can be taken together to form a 5-8 membered ring;

each R³ and R⁴ is independently H, C₁-C₆ alkyl, C₁-C₆ alkoxy,C(═O)—(C₁-C₆)-alkyl, C₁-C₆ haloalkyl, hydroxy, fluoro, chloro, bromo,iodo, nitro, or cyano; or CR³R⁴ is C═O;n=1, 2, 3 or 4;each R⁵ and R⁶ is independently H, C₁-C₆ alkyl, C₁-C₆ alkoxy,C(═O)—(C₁-C₆)-alkyl, C₁-C₆ haloalkyl, hydroxy, fluoro, chloro, bromo,iodo, nitro, or cyano; or CR⁵R⁶ is C═O or C═CH₂; or wherein —NR²—(CR⁵R⁶)_(p)— can be

Y is a bond, O, S, SO, SO₂, CH₂, NH, N(C₁-C₆ alkyl), or NHC(═O);Z is OH, NR⁶R⁷, NR⁸SO₂(C₁-C₆ alkyl), NR⁸C(O)NR⁶R⁷, NR⁸C(S)NR⁶R⁷,NR⁸C(O)O(C₁-C₆ alkyl), NR⁸-dihydrothiazole, or NR⁸-dihydroimidazole;wherein each R⁶, R⁷ and R⁸ is independently H, C₁-C₆ alkyl or C₆-C₁₂aralkyl; or

wherein R⁹ and R¹⁰ are each independently H, C₁-C₆ alkyl, aralkyl.

In specific embodiments of the Formula I when X is a bond, Y is O andAr² is phenyl, Z is not NR⁸SO₂(C₁-C₆ alkyl); and when X is O,—NR²—(CR⁵R⁶)_(p)— is not —NH—C(═O)—.

In one embodiment, when Y is NHC(═O), Z is not OH or NR⁸SO₂(C₁-C₆alkyl). In one subembodiment, when R¹ and R² are taken together to forma 5-8 membered ring so that —NR¹—(CR³R⁴)_(n)—NR²— is

Y—Ar² is not NH-heteroaryl. In another subembodiment, when R¹ and R² aretaken together to form a 5-8 membered ring so that —NR¹—(CR³R⁴)_(n)—NR²—is

Y is not NHC(═O).

In one embodiment, X is NR¹. In another embodiment, X is O. In anotherembodiment, X is a bond. In a particular subembodiment, X is a bond, nis 1, R³ and R⁴ are both H, and W is C₂ alkenyl. In certain embodiments,X is not a bond.

In particular subembodiment, Ar¹ is phenyl, pyridyl, pyrimidinyl,thiophenyl, imidazolyl, furanyl, indolyl, benzothiophenyl, benzofuranyl,or benzoimidazolyl.

In another particular subembodiment, L is C₁-C₄ alkyl, C₁-C₄ alkoxy,C(═O)—(C₁-C₄)-alkyl, C₁-C₆ haloalkyl, hydroxy, fluoro, chloro, bromo,iodo, nitro, or cyano. In a further subembodiment, L is methyl,trifluoromethyl, methoxy, nitro, fluoro, chloro or hydroxy. In onefurther subembodiment, there are one, two or three L groups substitutingAr¹. In one subembodiment, Ar¹ is substituted with one fluoro group. Inone subembodiment, Ar¹ is substituted with two fluoro groups. In onesubembodiment, Ar¹ is substituted with one fluoro group and one chlorogroup. In one subembodiment, Ar¹ is substituted with one chloro group.In one subembodiment, Ar¹ is substituted with two chloro groups. In onesubembodiment, Ar¹ is substituted with one methyl group. In onesubembodiment, Ar¹ is substituted with one trifluoromethyl group.

In one subembodiment, Ar¹ is phenyl. In one subembodiment, Ar¹ is phenyland is substituted with an L group at the 2, 3, or 4 position. Inanother subembodiment, Ar¹ is phenyl and is substituted with L groups atthe 2 and 4 positions. In another subembodiment, Ar¹ is phenyl and issubstituted with L groups at the 3 and 4 positions.

In one subembodiment, Ar¹ is pyridyl. In another subembodiment, Ar¹ is2-pyridyl, 3-pyridyl, or 4-pyridyl.

In one embodiment, Ar¹ is a bicyclic group wherein the W group isattached to the heterocyclic ring.

In one embodiment, W is a bond. In another embodiment, W is CH₂. Inanother embodiment, W is C₂-C₄ alkenyl.

In one embodiment, each R¹ and R² is independently H or C₁-C₄ alkyl, forexample, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl ortert-butyl. In one embodiment, R¹ and R² are both H. In one embodiment,R¹ and R² are both C₁-C₄ alkyl, for example n-butyl. In anotherembodiment, R¹ and R² can be taken together to form a 5-8 membered ringso that —NR¹—(CR³R⁴)_(n)—NR²— is

In one subembodiment, when R¹ and R² are taken together to form a 5-8membered ring so that —NR¹—(CR³R⁴)_(n)—NR²— is

Y—Ar² is not NH-heteroaryl. In another subembodiment, when R¹ and R² aretaken together to form a 5-8 membered ring so that —NR¹—(CR³R⁴)_(n)—NR²—is

Y is not NHC(═O). In one embodiment, n is 2. In one embodiment, n is 3.In another embodiment, R¹ and R² are each CH₂. In a subembodiment, CR³R⁴is CH₂ and n is 2. In a subembodiment, CR³R⁴ in CH₂ and n is 3. In asubembodiment, CR³R⁴ is C═O and n is 1.

In one embodiment,

In one embodiment,

In another embodiment,

In one embodiment, each R⁵ and R⁶ is independently H, C₁-C₄ alkyl, C₁-C₄alkoxy, C(═O)—(C₁-C₄)-alkyl, C₁-C₄ haloalkyl, hydroxy, fluoro, chloro,bromo, iodo, nitro, or cyano. In one embodiment, CR⁵R⁶ is C═O or C═CH₂.In one embodiment, p is 2, 3, or 4. In another embodiment, p is 3. Inone embodiment, R⁵ and R⁶ are H. In another embodiment, one of R⁵ and R⁶is hydroxy. In another embodiment, CR⁵R⁶ is C═CH₂. In anotherembodiment, CR⁵R⁶ is C═O. In one embodiment, (CR⁵R⁶)_(p) is selectedfrom the group consisting of

Compounds of Formula I can include compounds wherein when p is greaterthan 1, each (CR⁵R⁶) can be independently selected, for example, in oneembodiment p is 2 and one (CR⁵R⁶) is C═O and the other (CR⁵R⁶) is CH₂.In one embodiment, R⁵ is not fluoro. In another embodiment, R⁶ is notfluoro.

In one embodiment, —NR²—(CR⁵R⁶)_(p)— is

In a particular subembodiment, the compound is

In another particular subembodiment, the compound is

In one embodiment, Y is a bond, O or CH₂. In one embodiment, Y is O. Inanother embodiment, Y is CH₂. In one embodiment, Y is not NH. In anotherembodiment, Y is not NHC(═O).

In one embodiment, Ar² is aryl. In one embodiment, Ar² is aryl, but notphenyl or heteroaryl. In one embodiment Ar² is phenyl. In onesubembodiment, Ar² is phenyl and is substituted with a Z group at the 4position. In one embodiment, Ar² is not heteroaryl. In one embodiment,Ar² is aryl, but not phenyl or heteroaryl.

In one embodiment, Z is OH, NR⁶R⁷, NR⁸SO₂(C₁-C₆ alkyl), NR⁸C(O)NR⁶R⁷,NR⁸C(S)NR⁶R⁷, NR⁸C(O)O(C₁-C₆ alkyl), NR⁸-dihydrothiazole, orNR⁸-dihydroimidazole.

In one embodiment,

In one subembodiment,

In one subembodiment,

In one subembodiment, R⁹ and R¹⁰ are each H.

In one embodiment, Z is NR⁸C(O)NR⁶R⁷, for example NHC(O)NH₂ orNHC(O)N(CH₃)₂.

In another embodiment, Z and Ar² are taken together and selected fromthe group consisting of:

In one embodiment, the compound is a compound of Formula I, or apharmaceutically acceptable salt, ester, prodrug or derivative thereof,wherein:

L is C₁-C₆ alkyl, C₁-C₆ alkoxy, C(═O)—(C₁-C₆)-alkyl, C₁-C₆ haloalkyl,alkaryl, hydroxy, —O-alkyl, —O-aryl, —SH, —S-alkyl, —S-aryl, fluoro,chloro, bromo, iodo, nitro, or cyano; or two L groups may be takentogether with Ar¹ to form a dioxolane ring or a cyclobutane ring;k=0, 1, 2, 3, 4 or 5;Ar¹ is phenyl, pyridyl, pyrimidinyl, thiophenyl, imidazolyl, furanyl,indolyl, benzothiophenyl, benzofuranyl, benzoimidazolyl;Ar² is phenyl;W is a bond, C₁-C₄ alkyl, or C₂-C₄ alkenyl;each R¹ and R² is independently H, C₁-C₄ alkyl; or

R¹ and R² can be taken together to form a 5-8 membered ring;

each R³ and R⁴ is independently H, C₁-C₆ alkyl, C₁-C₆ alkoxy,C(═O)—(C₁-C₆)-alkyl, C₁-C₆ haloalkyl, hydroxy, fluoro, chloro, bromo,iodo, nitro, or cyano; or CR³R⁴ is C═O;n=1, 2, 3 or 4;each R⁵ and R⁶ is independently H, C₁-C₆ alkyl, C₁-C₆ alkoxy,C(═O)—(C₁-C₆)-alkyl, C₁-C₆ haloalkyl, hydroxy, fluoro, chloro, bromo,iodo, nitro, or cyano; or CR⁵R⁶ is C═O, C═CH₂;Y is a bond, O, S, SO, SO₂, CH₂, NH, N(C₁-C₆ alkyl), NHC(═O);Z is OH, NH₂, NHSO₂(C₁-C₄ alkyl), NHC(O)NR⁶R⁷, NR⁸C(S)NR⁶R⁷,NHC(O)O(C₁-C₄ alkyl), NH-dihydrothiazole, or NH-dihydroimidazole;wherein each R⁶ and R⁷ is independently H, C₁-C₆ alkyl; or

wherein R⁹ and R¹⁰ are each independently H or C₁-C₄ alkyl.

In one embodiment, the compound is a compound of Formula I, or apharmaceutically acceptable salt, ester, prodrug or derivative thereof,wherein:

L is C₁-C₆ alkyl, C₁-C₆ alkoxy, C(═O)—(C₁-C₆)-alkyl, C₁-C₆ haloalkyl,alkaryl, hydroxy, —O-alkyl, —O-aryl, —SH, —S-alkyl, —S-aryl, fluoro,chloro, bromo, iodo, nitro, or cyano; or two L groups may be takentogether with Ar¹ to form a dioxolane ring or a cyclobutane ring;k=0, 1, 2, 3, 4 or 5;Ar¹ is phenyl, pyridyl, pyrimidinyl, thiophenyl, imidazolyl, furanyl,indolyl, benzothiophenyl, benzofuranyl, benzoimidazolyl;Ar² is phenyl;W is a bond, C₁-C₄ alkyl, or C₂-C₄ alkenyl;each R¹ and R² is independently H, C₁-C₄ alkyl; or

R¹ and R² can be taken together to form a 5-8 membered ring;

each R³ and R⁴ is independently H, C₁-C₆ alkyl, C₁-C₆ alkoxy,C(═O)—(C₁-C₆)-alkyl, C₁-C₆ haloalkyl, hydroxy, fluoro, chloro, bromo,iodo, nitro, or cyano; or CR³R⁴ is C═O;n=1, 2, 3 or 4;each R⁵ and R⁶ is independently H, C₁-C₆ alkyl, C₁-C₆ alkoxy,C(═O)—(C₁-C₆)-alkyl, C₁-C₆ haloalkyl, hydroxy, fluoro, chloro, bromo,iodo, nitro, or cyano; or CR⁵R⁶ is C═O, C═CH₂;Y is a bond, O, S, SO, SO₂, CH₂, NH, N(C₁-C₆ alkyl), NHC(═O);Z is OH, NH₂, NHSO₂(C₁-C₄ alkyl), NHC(O)NR⁶R⁷, NR⁸C(S)NR⁶R⁷,NHC(O)O(C₁-C₄ alkyl), NH-dihydrothiazole, or NH-dihydroimidazole;wherein each R⁶ and R⁷ is independently H, C₁-C₆ alkyl; or

wherein R⁹ and R¹⁰ are each independently H or C₁-C₄ alkyl.

In one embodiment, the compound is a compound of Formula I, or apharmaceutically acceptable salt, ester, prodrug or derivative thereof,wherein:

L is C₁-C₄ alkyl, C₁-C₄ alkoxy, C(═O)—(C₁-C₄)-alkyl, C₁-C₄ haloalkyl,alkaryl, hydroxy, —O-alkyl, —O-aryl, —SH, —S-alkyl, —S-aryl, fluoro,chloro, bromo, iodo, or nitro; ortwo L groups may be taken together to form a dioxolane ring with Ar¹;k=0, 1, 2, 3, 4 or 5;Ar¹ is phenyl or pyridyl;Ar² is phenyl;W is a bond or C₁-C₄ alkyl;

X is NR¹;

each R¹ and R² is independently H or C₁-C₄ alkyl; or

R¹ and R² can be taken together to form a 5-8 membered ring;

each R³ and R⁴ is independently H or C₁-C₄ alkyl; or CR³R⁴ is C═O;n=2 or 3;each R⁵ and R⁶ is independently H, C₁-C₄ alkyl or OH; or CR⁴R⁵ is C═O orC═CH₂;

Y is O or CH₂;

Z is OH, NH₂, NHSO₂(C₁-C₄ alkyl), NHC(O)NR⁶R⁷, NR⁸C(S)NR⁶R⁷,NHC(O)O(C₁-C₄ alkyl), NH-dihydrothiazole, or NH-dihydroimidazole;wherein each R⁶ and R⁷ is independently H or C₁-C₄ alkyl; or

R⁹ is H or C₁-C₄ alkyl.

In one embodiment, the compound is a compound of Formula I, or apharmaceutically acceptable salt, ester, prodrug or derivative thereof,wherein:

L is C₁-C₄ alkyl, C₁-C₄ alkoxy, C(═O)—(C₁-C₄)-alkyl, C₁-C₄ haloalkyl,alkaryl, hydroxy, —O-alkyl, —O-aryl, —SH, —S-alkyl, —S-aryl, fluoro,chloro, bromo, iodo, or nitro; ortwo L groups may be taken together to form a dioxolane ring with Ar¹;k=0, 1, 2, 3, 4 or 5;Ar¹ is phenyl or pyridyl;Ar² is phenyl;W is a bond or C₁-C₄ alkyl;

X is O;

R² is H or C₁-C₄ alkyl;each R³ and R⁴ is independently H or C₁-C₄ alkyl; or CR³R⁴ is C═O;n=2 or 3;each R⁵ and R⁶ is independently H, C₁-C₄ alkyl or OH; or CR⁴R⁵ is C═O orC═CH₂;

Y is O or CH₂;

Z is OH, NH₂, NHSO₂(C₁-C₄ alkyl), NHC(O)NR⁶R⁷, NHC(O)O(C₁-C₄ alkyl),NH-dihydrothiazole, or NH-dihydroimidazole; wherein each R⁶ and R⁷ isindependently H or C₁-C₄ alkyl; or

R⁹ is H or C₁-C₄ alkyl.

In one embodiment, the compound is a compound of Formula I, or apharmaceutically acceptable salt, ester, prodrug or derivative thereof,wherein:

L is C₁-C₄ alkyl, C₁-C₄ alkoxy, C(═O)—(C₁-C₄)-alkyl, C₁-C₄ haloalkyl,hydroxy, fluoro, chloro, bromo, iodo, or nitro; ortwo L groups may be taken together to form a dioxolane ring with Ar¹;k=0, 1, 2, 3, 4 or 5;Ar¹ is phenyl or pyridyl;Ar² is phenyl;W is C₂-C₄ alkenyl;X is a bond;R² is H or C₁-C₄ alkyl;each R³ and R⁴ is independently H or C₁-C₄ alkyl; or CR³R⁴ is C═O;n=1, 2 or 3;each R⁵ and R⁶ is independently H, C₁-C₄ alkyl or OH; or CR⁴R⁵ is C═O orC═CH₂;

Y is O or CH₂;

Z is OH, NH₂, NHSO₂(C₁-C₄ alkyl), NHC(O)NR⁶R⁷, NR⁸C(S)NR⁶R⁷,NHC(O)O(C₁-C₄ alkyl), NH-dihydrothiazole, or NH-dihydroimidazole;wherein each R⁶ and R⁷ is independently H or C₁-C₄ alkyl; or

R⁹ is H or C₁-C₄ alkyl.

In one embodiment, the compound is selected from the compounds in Table1.

TABLE 1 Compound NAME

N-(4-{3-[4-(3,4-Dichloro-phenyl)-piperazin-1-yl]-2-(S)-hydroxy-propoxy}-phenyl)-methanesulfonamide

N-(4-{3-[4-(4-Chloro-phenyl)-piperazin-1-yl]-2-(S)-hydroxy-propoxy}-phenyl)-methanesulfonamide

N-(4-{3-[4-phenyl-piperazin-1-yl]-2-(S)-hydroxy-propoxy}-phenyl)-methanesulfonamide

N-(4-{3-[4-(4-Hydroxy-phenyl)-piperazin-1-yl]-2-(S)-hydroxy-propoxy}-phenyl)-methanesulfonamide

N-(4-{3-4-(2-Pyridyl)-piperazin-1-yl]-2-(S)-hydroxy-propoxy}-phenyl)-methanesulfonamide

N-(4-{3-[4-(4-Pyridyl)-piperazin-1-yl]-2-(S)-hydroxy-propoxy}-phenyl)-methanesulfonamide

N-{4-[2-(S)-Hydroxy-3-(2-phenylamino-ethylamino)-propoxy]-phenyl}-methanesulfonamide

N-{4-[2-(S)-Hydroxy-3-(2-(3,4-difluoro-phenyl)amino-ethylamino)-propoxy]-phenyl}- methanesulfonamide

N-(4-{3-[3-(3,4-Dichloro-phenyl)-allylamino]-2-(S)-hydroxy-propoxy}-phenyl)-methanesulfonamide

N-[4-(3-{Butyl-[3-(3,4-dichloro-phenyl)-allyl]-amino}-2-(S)-hydroxy-propoxy)-phenyl]- methanesulfonamide

N-(4-{3-[3-(3,4-Difluoro-phenyl)-allylamino]-2-(S)-hydroxy-propoxy}-phenyl)-methanesulfonamide

In one embodiment, the compound is selected from the compounds in Table2.

TABLE 2 Compound NAME

6-{3-[4-(3,4-Difluoro-phenyl)-piperazin-1-yl]-2-(S)-hydroxy-propoxy}-3H-benzooxazol-2-one

6-{3-[4-(3,4-Dichloro-phenyl)-piperazin-1-yl]-2-(S)-hydroxy-propoxy}-3H-benzooxazol-2-one

6-{3-[4-(4-Methyl-phenyl)-piperazin-1-yl]-2-(S)-hydroxy-propoxy}-3H-benzooxazol-2-one

6-{3-[2-(4-Chloro-phenylamino)-ethylamino]-2-(S)-hydroxy-propoxy}-3H-benzooxazol-2-one

In one embodiment, the compound is selected from the compounds in Table3.

TABLE 3 Compound NAME

4-{3-[4-(3,4-Dichloro-phenyl)-piperazin-1-yl]-2-(S)-hydroxy-propoxy}-phenol

4-{3-[4-(3,4-Difluoro-phenyl)-piperazin-1-yl]-2-(S)-hydroxy-propoxy}-phenol

4-{3-[4-(3,4-Difluoro-phenyl)-piperazin-1-yl]-2-(R)-hydroxy-propoxy}-phenol

4-{3-[4-(4-Fluoro-phenyl)-piperazin-1-yl]-2-(S)- hydroxy-propoxy}-phenol

4-{3-[4-(3,4-Dimethyl-phenyl)-piperazin-1-yl]-2-(S)-hydroxy-propoxy}-phenol

4-{3-[4-(4-Methyl-phenyl)-piperazin-1-yl]-2-(S)- hydroxy-propoxy}-phenol

4-{3-[4-(4-Cyano-phenyl)-piperazin-1-yl]-2-(S)- hydroxy-propoxy}-phenol

4-{3-[4-(4-Bromo-phenyl)-piperazin-1-yl]-2-(S)- hydroxy-propoxy}-phenol

4-{3-[4-(4-Hydroxy-phenyl)-piperazin-1-yl]-2-(S)-hydroxy-propoxy}-phenol

4-{3-[4-(4-Methoxy-phenyl)-piperazin-1-yl]-2-(S)-hydroxy-propoxy}-phenol

4-{3-[4-(4-Trifluoromethyl-phenyl)-piperazin-1-yl]-2-(S)-hydroxy-propoxy}-phenol

4-{3-[4-(4-Biphenyl)-piperazin-1-yl]-2-(S)- hydroxy-propoxy}-phenol

4-{3-[4-(2,4-Difluoro-phenyl)-piperazin-1-yl]-2-(S)-hydroxy-propoxy}-phenol

4-{3-[4-(2-Fluoro-phenyl)-piperazin-1-yl]-2-(S)- hydroxy-propoxy}-phenol

4-{3-[4-(2-Chloro-phenyl)-piperazin-1-yl]-2-(S)- hydroxy-propoxy}-phenol

4-{3-[4-(2-Chloro-phenyl)-piperazin-1-yl]-2-(S)- hydroxy-propoxy}-phenol

4-{3-[4-(2-Cyano-phenyl)-piperazin-1-yl]-2-(S)- hydroxy-propoxy}-phenol

4-{3-[4-Phenyl-piperazin-1-yl]-2-(S)-hydroxy- propoxy}-phenol

4-{3-[4-(3-Fluoro-phenyl)-piperazin-1-yl]-2-(S)- hydroxy-propoxy}-phenol

4-{3-[4-(3-Chloro-phenyl)-piperazin-1-yl]-2-(S)- hydroxy-propoxy}-phenol

4-{3-[4-(3-Methyl-phenyl)-piperazin-1-yl]-2-(S)- hydroxy-propoxy}-phenol

4-{3-[4-(3-Trifluoromethyl-phenyl)-piperazin-1-yl]-2-(S)-hydroxy-propoxy}-phenol

In one embodiment, the compound is selected from the compounds in Table4.

TABLE 4 Compound NAME

(4-{2-[4-(3,4-Difluoro-phenyl)-piperazin-1-ylmethyl]-allyloxy}-phenyl)-urea

(4-{3-[4-(4-Fluoro-phenyl)-piperazin-1-yl]- propoxy}-phenyl)-urea

(4-{3-[4-(4-Chloro-phenyl)-piperazin-1-yl]-2-hydroxy-propoxy}-phenyl)-urea

1-Ethyl-3-(4-{3-[4-(4-fluoro-phenyl)-piperazin-1-yl]-propoxyl}-phenyl)-urea

(4-{3-[4-(4-Fluoro-phenyl)-piperazin-1-yl]- propoxy}-phenyl)-carbamicacid methyl ester

(S)-1-(4-(3-(4-(3,4-dichlorophenyl)piperazin-1-yl)-2-hydroxypropoxy)phenyl)urea

(S)-1-(4-(3-(4-(3,4-difluorophenyl)piperazin-1-yl)-2-hydroxypropoxy)phenyl)urea

(R)-1-(4-(3-(4-(3,4-difluorophenyl)piperazin-1-yl)-2-hydroxypropoxy)phenyl)urea

(S)-1-(4-(3-(4-(4-fluorophenyl)piperazin-1-yl)-2-hydroxypropoxy)phenyl)urea

(S)-1-(4-(3-(4-(3,4-dimethylphenyl)piperazin-1-yl)-2-hydroxypropoxy)phenyl)urea

(S)-1-(4-(2-hydroxy-3-(4-p-tolylpiperazin-1- yl)propoxy)phenyl)urea

(S)-1-(4-(3-(4-(4-cyanophenyl)piperazin-1-yl)-2-hydroxypropoxy)phenyl)urea

(S)-1-(4-(3-(4-(4-bromophenyl)piperazin-1-yl)-2-(S)-hydroxypropoxy)phenyl)urea

(S)-1-(4-(2-hydroxy-3-(4-(4-hydroxyphenyl)piperazin-1-yl)propoxy)phenyl)urea

(S)-1-(4-(2-hydroxy-3-(4-(4-methoxyphenyl)piperazin-1-yl)propoxy)phenyl)urea

(S)-1-(4-(2-hydroxy-3-(4-(4- (trifluoromethyl)phenyl)piperazin-1-yl)propoxy)phenyl)urea

(S)-1-(4-(3-(4-(biphenyl-4-yl)piperazin-1-yl)-2-hydroxypropoxy)phenyl)urea

(S)-1-(4-(3-(4-(2,4-difluorophenyl)piperazin-1-yl)-2-hydroxypropoxy)phenyl)urea

(S)-1-(4-(3-(4-(2-fluorophenyl)piperazin-1-yl)-2-hydroxypropoxy)phenyl)urea

(S)-1-(4-(3-(4-(2-chlorophenyl)piperazin-1-yl)-2-hydroxypropoxy)phenyl)urea

(S)-1-(4-(2-hydroxy-3-(4-o-tolylpiperazin-1- yl)propoxy)phenyl)urea

(S)-1-(4-(3-(4-(2-cyanophenyl)piperazin-1-yl)-2-hydroxypropoxy)phenyl)urea

(S)-1-(4-(2-hydroxy-3-(4-phenylpiperazin-1- yl)propoxy)phenyl)urea

(S)-1-(4-(3-(4-(3-fluorophenyl)piperazin-1-yl)-2-hydroxypropoxy)phenyl)urea

(S)-1-(4-(3-(4-(3-chlorophenyl)piperazin-1-yl)-2-(S)-hydroxypropoxy)phenyl)urea

(S)-1-(4-(2-hydroxy-3-(4-m-tolypiperazin-1- yl)propoxy)phenyl)urea

(S)-1-(4-(2-hydroxy-3-(4-(3- (trifluoromethyl)phenyl)piperazin-1-yl)propoxy)phenyl)urea

(S)-1-(4-(3-(4-(4-ethylphenyl)piperazin-1-yl)-2-hydroxypropoxy)phenyl)urea

(S)-1-(4-(3-(4-(4-isopropylphenyl)piperazin-1-yl)-2-hydroxypropoxy)phenyl)urea

(S)-1-(4-(3-(4-(4-cyclopropylphenyl)piperazin-1-yl)-2-hydroxypropoxy)phenyl)urea

(S)-1-(4-(3-(4-(4-propylphenyl)piperazin-1-yl)-2-hydroxypropoxy)phenyl)urea

(S)-1-(4-(3-(4-(4-butylphenyl)piperazin-1-yl)-2-hydroxypropoxy)phenyl)urea

(S)-1-(4-(3-(4-(4-isobutylphenyl)piperazin-1-yl)-2-hydroxypropoxy)phenyl)urea

(S)-1-(4-(2-hydroxy-3-(4-(4-(prop-1-ynyl)phenyl)piperazin-1-yl)propoxy)phenyl)urea

(S)-1-(4-(3-(4-(2-naphthyl)piperazin-1-yl)-2- hydroxypropoxy)phenyl)urea

1-(4-((S)-3-((R)-4-(4-chlorophenyl)-2- methylpiperazin-1-yl)-2-hydroxypropoxy)phenyl)urea

1-(4-((S)-3-((S)-4-(4-chlorophenyl)-2- methylpiperazin-1-yl)-2-hydroxypropoxy)phenyl)urea

1-(4-((S)-3-4-(4-chlorophenyl)-cis-2,6- dimethylpiperazin-1-yl)-2-hydroxypropoxy)phenyl)urea

1-(4-((S)-3-(cis-2,6-dimethyl-4-p-tolylpiperazin-1-yl)-2-hydroxypropoxy)phenyl)urea

(R)-1-(4-(3-(4-(4-chlorophenyl)piperazin-1-yl)-2-hydroxypropoxy)phenyl)urea

(R)-1-(4-(3-(4-(3,4-dichlorophenyl)piperazin-1-yl)-2-hydroxypropoxy)phenyl)urea

(R)-1-(4-(3-(4-(4-ethylphenyl)piperazin-1-yl)-2-hydroxypropoxy)phenyl)urea

(R)-1-(4-(3-(4-(4-isopropylphenyl)piperazin-1-yl)-2-hydroxypropoxy)phenyl)urea

(R)-1-(4-(3-(4-(4-cyclopropylphenyl)piperazin-1-yl)-2-hydroxypropoxy)phenyl)urea

(R)-1-(4-(3-(4-(4-propylphenyl)piperazin-1-yl)-2-hydroxypropoxy)phenyl)urea

(R)-1-(4-(3-(4-(4-butylphenyl)piperazin-1-yl)-2-hydroxypropoxy)phenyl)urea

(R)-1-(4-(3-(4-(4-isobutylphenyl)piperazin-1-yl)-2-hydroxypropoxy)phenyl)urea

(R)-1-(4-(2-hydroxy-3-(4-(4-(prop-1-ynyl)phenyl)piperazin-1-yl)propoxy)phenyl)urea

(R)-1-(4-(3-(4-(2-naphthyl)piperazin-1-yl)-2- hydroxypropoxy)phenyl)urea

(R)-1-(4-(3-(4-(4-methylphenyl)piperazin-1-yl)-2-hydroxypropoxy)phenyl)urea

(R)-1-(4-(3-(4-phenyl-piperazin-1-yl)-2- hydroxypropoxy)phenyl)urea

(R)-1-(4-(3-(4-(4-fluorophenyl)piperazin-1-yl)-2-hydroxypropoxy)phenyl)urea

In one embodiment, the compound is selected from the compounds in Table5.

TABLE 5 Compound Name

N-[2-(3,4-Dichloro-phenylamino)-ethyl]-2-(4-methanesulfonylamino-phenoxy)-acetamide

N-(4-{2-[2-(3,4-Dichloro-phenylamino)- ethylamino]-ethoxy}-phenyl)-methanesulfonamide

N-(4-{3-[4-(3,4-Dichloro-phenyl)-piperazin-1-yl]-3-oxo-propyl}-phenyl)-methanesulfonamide

N-(4-{3-[4-(3,4-DiFluoro-phenyl)-piperazin-1-yl]-3-oxo-propyl}-phenyl)-methanesulfonamide

N-(4-{3-[4-(3,4-Dichloro-phenyl)-piperazin-1-yl]-propyl}-phenyl)-methanesulfonamide

N-(4-{2-[4-(3,4-Dichloro-phenyl)-piperazin-1- yl]-2-oxo-ethoxy}-phenyl)-methanesulfonamide

6-{2-[4-(3,4-Dichloro-phenyl)-piperazin-1-yl]-2-oxo-ethoxy}-3H-benzooxazol-2-one

6-{2-[4-(3,4-DiFluoro-phenyl)-piperazin-1-yl]-2-oxo-ethoxy}-3H-benzooxazol-2-one

6-{2-[4-(4-Chloro-phenyl)-piperazin-1-yl]-2-oxo-ethoxy}-3H-benzooxazol-2-one

N-[2-(3,4-Dichloro-phenylamino)-ethyl]-2-(2-oxo-2,3-dihydro-benzooxazol-6-yloxy)- acetamide

N-[2-(3,4-Dichloro-phenylamino)-ethyl]-2-(4- hydroxy-phenoxy)-acetamide

N-[2-(3,4-Dichloro-phenylamino)-ethyl-(4- hydroxy-phenyl)-propionamide

N-[2-(3,4-Dichloro-phenylamino)-ethyl]-2-(3-fluoro-4-hydroxy-phenoxy)-acetamide

N-[3-(3,4-Dichloro-phenyl)-allyl]-2-(4-methanesulfonylamino-phenoxy)-acetamide

N-[2-(3,4-Dichloro-phenoxy)-ethyl]-2-(4-methanesulfonylamino-phenoxy)-acetamide

N-[2-(3,4-Dichloro-phenoxy)-ethyl]-2-(4- hydroxy-phenoxy)-acetamide

N-[2-(3,4-Dichloro-phenoxy)-ethyl]-2-(4- ureido-phenoxy)-acetamide

(S)-1-(4-chlorophenyl)-3-(2-hydroxy-3-(4-hydroxyphenoxy)propyl)imidazolidin-2-one

(S)-N-(4-(3-(3-(3,4-dichlorophenyl)-2- oxoimidazolidin-1-yl)-2-hydroxypropoxy)phenyl)methanesulfonamide

(S)-3-(2-(4-chlorophenylamino)ethyl)-5-((4-hydroxyphenoxy)methyl)oxazolidin-2-one

(S)-N-(4-((3-(2-(3,4- dichlorophenylamino)ethyl)-2-oxooxazolidin-5-yl)methoxy)phenyl)methanesulfonamide

In one embodiment, the compound is selected from Table 6.

TABLE 6 Compound NAME

(S)-5-(3-(4-(3,4-dichlorophenyl)piperazin-1-yl)-2-hydroxypropoxy)indolin-2-one

(S)-5-(3-(4-(3,4-difluorophenyl)piperazin-1-yl)-2-hydroxypropoxy)indolin-2-one

(R)-5-(3-(4-(3,4-difluorophenyl)piperazin-1-yl)-2-hydroxypropoxy)indolin-2-one

(S)-5-(3-(4-(4-fluorophenyl)piperazin-1-yl)-2-hydroxypropoxy)indolin-2-one

(S)-5-(3-(4-(3,4-dimethylphenyl)piperazin-1-yl)-2-hydroxypropoxy)indolin-2-one

(S)-5-(2-hydroxy-3-(4-p-tolylpiperazin-1- yl)propoxy)indolin-2-one

(S)-4-(4-(2-hydroxy-3-(2-oxoindolin-5-yloxy)propyl)piperazin-1-yl)benzonitrile

(S)-5-(3-(4-(4-bromophenyl)piperazin-1-yl)-2-hydroxypropoxy)indolin-2-one

(S)-5-(2-hydroxy-3-(4-(4-hydroxyphenyl)piperazin-1-yl)propoxy)indolin-2-one

(S)-5-(2-hydroxy-3-(4-(4-methoxyphenyl)piperazin-1-yl)propoxy)indolin-2-one

(S)-5-(2-hydroxy-3-(4-(4- (trifluoromethyl)phenyl)piperazin-1-yl)propoxy)indolin-2-one

(S)-5-(3-(4-(biphenyl-4-yl)piperazin-1-yl)-2-hydroxypropoxy)indolin-2-one

(S)-5-(3-(4-(2,4-difluorophenyl)piperazin-1-yl)-2-hydroxypropoxy)indolin-2-one

(S)-5-(3-(4-(2-fluorophenyl)piperazin-1-yl)-2-hydroxypropoxy)indolin-2-one

(S)-5-(3-(4-(2-chlorophenyl)piperazin-1-yl)-2-hydroxypropoxy)indolin-2-one

(S)-5-(2-hydroxy-3-(4-o-tolylpiperazin-1- yl)propoxy)indolin-2-one

(S)-2-(4-(2-hydroxy-3-(2-oxoindolin-5-yloxy)propyl)piperazin-1-yl)benzonitrile

(S)-5-(2-hydroxy-3-(4-phenylpiperazin-1- yl)propoxy)indolin-2-one

(S)-5-(3-(4-(3-fluorophenyl)piperazin-1-yl)-2-hydroxypropoxy)indolin-2-one

(S)-5-(3-(4-(3-chlorophenyl)piperazin-1-yl)-2-hydroxypropoxy)indolin-2-one

(S)-5-(2-hydroxy-3-(4-m-tolypiperazin-1- yl)propoxy)indolin-2-one

(S)-5-(2-hydroxy-3-(4-(3- (trifluoromethyl)phenyl)piperazin-1-yl)propoxy)indolin-2-one

(S)-(3-(4-(4-ethylphenyl)piperazin-1-yl) hydroxypropoxy)indolin-2-one

(S)-5-(2-hydroxy-3-(4-(4--isopropylphenyl)piperazin-1-yl)propoxy)indolin-2-one

(S)-5-(3-(4-(4-cyclopropylphenyl)piperazin-1-yl)-2-hydroxypropoxy)indolin-2-one

(S)-5-(2-hydroxy-3-(4-(4-propylphenyl)piperazin-1-yl)propoxy)indolin-2-one

(S)-5-(3-(4-(4-butylphenyl)piperazin-1-yl)-2-hydroxypropoxy)indolin-2-one

(S)-5-(2-hydroxy-(3-(4-(4-isobutylphenyl)piperazin-1-yl)propoxy)indolin-2-one

(S)-5-(2-hydroxy-3-(4-(4-(prop-1-ynyl)phenyl)piperazin-1-yl)propoxy)indolin-2-one

(S)-5-(2-hydroxy-3-(4-(naphthalen-2-yl)piperazin-1-yl)propoxy)indolin-2-one

5-((S)-3-((R)-4-(4-chlorophenyl)-2-methylpiperazin-1-yl)-2-hydroxypropoxy)indolin-2-one

5-((S)-3-((S)-4-(4-chlorophenyl)-2-methylpiperazin-1-yl)-2-hydroxypropoxy)indolin-2-one

5-((S)-3-((2S,6R)-4-(4-chlorophenyl)-2,6-dimethylpiperazin-1-yl)-2-hydroxypropoxy)indolin-2- one

5-((S)-3-((2S,6R)-2,6-dimethyl-4-p-tolylpiperazin-1-yl)-2-hydroxypropoxy)indolin-2-one

(R)-5-(3-(4-(4-chlorophenyl)piperazin-1-yl)-2-hydroxypropoxy)indolin-2-one

(R)-5-(3-(4-(3,4-dichlorophenyl)piperazin-1-yl)-2-hydroxypropoxy)indolin-2-one

(R)-5-(3-(4-(4-ethylphenyl)piperazin-1-yl) hydroxypropoxy)indolin-2-one

(R)-5-(2-hydroxy-3-(4-(4-isopropylphenyl)piperazin-1-yl)propoxy)indolin-2-one

(R)-5-(3-(4-(4-cyclopropylphenyl)piperazin-1-yl)-2-hydroxypropoxy)indolin-2-one

(R)-5-(2-hydroxy-3-(4-(4-propylphenyl)piperazin-1-yl)propoxy)indolin-2-one

(R)-5-(3-(4-(4-butylphenyl)piperazin-1-yl)-2-hydroxypropoxy)indolin-2-one

(R)-5-(2-hydroxy-3-(4-(4-isobutylphenyl)piperazin-1-yl)propoxy)indolin-2-one

(R)-5-(2-hydroxy-3-(4-(4-(prop-1-ynyl)phenyl)piperazin-1-yl)propoxy)indolin-2-one

(R)-5-(2-hydroxy-3-(4-(naphthalen-2-yl)piperazin-1-yl)propoxy)indolin-2-one

(R)-5-(2-hydroxy-(3-(4-p-tolylpiperazin-1- yl)propoxy)indolin-2-one

(R)-5-(2-hydroxy-3-(4-phenylpiperazin-1- yl)propoxy)indolin-2-one

(R)-5-(3-(4-(4-fluorophenyl)piperazin-1-yl)-2-hydroxypropoxy)indolin-2-one

In one embodiment, the compound is selected from Table 7.

TABLE 7 Compound NAME

(S)-6-(3-(4-(3,4-dichlorophenyl)piperazin-1-yl)-2-hydroxypropoxy)-3,4-dihydroquinolin-2(1H)-one

(S)-6-(3-(4-(3,4-difluorophenyl)piperazin-1-yl)-2-hydroxypropoxy)-3,4-dihydroquinolin-2(1H)-one

(S)-6-(3-(4-(3,4-difluorophenyl)piperazin-1-yl)-2-hydroxypropoxy)-3,4-dihydroquinolin-2(1H)-one

(S)-6-(3-(4-(4-fluorophenyl)piperazin-1-yl)-2-hydroxypropoxy)-3,4-dihydroquinolin-2(1H)-one

(S)-6-(3-(4-(3,4-dimethylphenyl)piperazin-1-yl)-2-hydroxypropoxy)-3,4-dihydroquinolin-2(1H)-one

(S)-6-(2-hydroxy-3-(4-p-tolylpiperazin-1-yl)propoxy)-3,4-dihydroquinolin-2(1H)-one

(S)-4-(4-(2-hydroxy-3-(2-oxo-1,2,3,4-tetrahydroquinolin-6-yloxy)propyl)piperazin-1- yl)benzonitrile

(S)-6-(3-(4-(4-bromophenyl)piperazin-1-yl)-2-hydroxypropoxy)-3,4-dihydroquinolin-2(1H)-one

(S)-6-(2-hydroxy-3-(4-(4-hydroxyphenyl)piperazin-1-yl)propoxy)-3,4-dihydroquinolin-2(1H)-one

(S)-6-(2-hydroxy-3-(4-(4-methoxyphenyl)piperazin-1-yl)propoxy)-3,4-dihydroquinolin-2(1H)-one

(S)-6-(2-hydroxy-3-(4-(4-(trifluoromethyl)phenyl)piperazin-1-yl)propoxy)-3,4-dihydroquinolin-2(1H)-one

(S)-6-(3-(4-(biphenyl-4-yl)piperazin-1-yl)-2-hydroxypropoxy)-3,4-dihydroquinolin-2(1H)-one

(S)-6-(3-(4-(2,4-difluorophenyl)piperazin-1-yl)-2-hydroxypropoxy)-3,4-dihydroquinolin-2(1H)-one

(S)-6-(3-(4-(2-fluorophenyl)piperazin-1-yl)-2-hydroxypropoxy)-3,4-dihydroquinolin-2(1H)-one

(S)-6-(3-(4-(2-chlorophenyl)piperazin-1-yl)-2-hydroxypropoxy)-3,4-dihydroquinolin-2(1H)-one

(S)-6-(2-hydroxy-3-(4-o-tolylpiperazin-1-yl)propoxy)-3,4-dihydroquinolin-2(1H)-one

(S)-2-(4-(2-hydroxy-3-(2-oxo-1,2,3,4-tetrahydroquinolin-6-yloxy)propyl)piperazin-1- yl)benzonitrile

(S)-6-(2-hydroxy-3-(4-phenylpiperazin-1-yl)propoxy)-3,4-dihydroquinolin-2(1H)-one

(S)-6-(3-(4-(3-fluorophenyl)piperazin-1-yl)-2-hydroxypropoxy)-3,4-dihydroquinolin-2(1H)-one

(S)-6-(3-(4-(3-chlorophenyl)piperazin-1-yl)-2-hydroxypropoxy)-3,4-dihydroquinolin-2(1H)-one

(S)-6-(2-hydroxy-3-(4-m-tolypiperazin-1-yl)propoxy)-3,4-dihydroquinolin-2(1H)-one

(S)-6-(2-hydroxy-3-(4-(3-(trifluoromethyl)phenyl)piperazin-1-yl)propoxy)-3,4-dihydroquinolin-2(1H)-one

(S)-6-(3-(4-(4-ethylphenyl)piperazin-1-yl)-2-hydroxypropoxy)-3,4-dihydroquinolin-2(1H)-one

(S)-6-(2-hydroxy-3-(4-(4-isopropylphenyl)piperazin-1-yl)propoxy)-3,4-dihydroquinolin-2(1H)-one

(S)-6-(3-(4-(4-cyclopropylphenyl)piperazin-1-yl)-2-hydroxypropoxy)-3,4-dihydroquinolin-2(1H)-one

(S)-6-(2-hydroxy-3-(4-(4-propylphenyl)piperazin-1-yl)propoxy)-3,4-dihydroquinolin-2(1H)-one

(S)-6-(3-(4-(4-butylphenyl)piperazin-1-yl)-2-hydroxypropoxy)-3,4-dihydroquinolin-2(1H)-one

(S)-6-(2-hydroxy-3-(4-(4-isobutylphenyl)piperazin-1-yl)propoxy)-3,4-dihydroquinolin-2(1H)-one

(S)-6-(2-hydroxy-3-(4-(4-(prop-1-ynyl)phenyl)piperazin-1-yl)propoxy)-3,4- dihydroquinolin-2(1H)-one

(S)-6-(2-hydroxy-3-(4-(naphthalen-2-yl)-piperazin-1-yl)propoxy)-3,4-dihydroquinolin-2(1H)-one

6-((S)-3-((R)-4-(4-chlorophenyl)-2-methylpiperazin-1-yl)-2-hydroxypropoxy)-3,4-dihydroquinolin-2(1H)- one

6-((S)-3-((S)-4-(4-chlorophenyl)-2-methylpiperazin-1-yl)-2-hydroxypropoxy)-3,4-dihydroquinolin-2(1H)- one

6-((S)-3-((2S,6R)-4-(4-chlorophenyl)-2,6-dimethylpiperazin-1-yl)-2-hydroxypropoxy)-3,4- dihydroquinolin-2(1H)-one

6-((S)-3-((2S,6R)-2,6-dimethyl-4-p-tolylpiperazin-1-yl)-2-hydroxypropoxy)-3,4-dihydroquinolin-2(1H)- one

(R)-6-(3-(4-(4-chlorophenyl)piperazin-1-yl)-2-hydroxypropoxy)-3,4-dihydroquinolin-2(1H)-one

(R)-6-(3-(4-(3,4-dichlorophenyl)piperazin-1-yl)-2-hydroxypropoxy)-3,4-dihydroquinolin-2(1H)-one

(R)-6-(3-(4-(4-ethylphenyl)piperazin-1-yl)-2-hydroxypropoxy)-3,4-dihydroquinolin-2(1H)-one

(R)-6-(2-hydroxy-3-(4-(4-isopropylphenyl)piperazin-1-yl)propoxy)-3,4-dihydroquinolin-2(1H)-one

(R)-6-(3-(4-(4-cyclopropylphenyl)piperazin-1-yl)-2-hydroxypropoxy)-3,4-dihydroquinolin-2(1H)-one

(R)-6-(2-hydroxy-3-(4-(4-propylphenyl)piperazin-1-yl)propoxy)-3,4-dihydroquinolin-2(1H)-one

(R)-6-(3-(4-(4-butylphenyl)piperazin-1-yl)-2-hydroxypropoxy)-3,4-dihydroquinolin-2(1H)-one

(R)-6-(2-hydroxy-3-(4-(4-isobutylphenyl)piperazin-1-yl)propoxy)-3,4-dihydroquinolin-2(1H)-one

(R-6-(2-hydroxy-3-(4-(4-(prop-1-ynyl)phenyl)piperazin-1-yl)propoxy)-3,4- dihydroquinolin-2(1H)-one

(R)-6-(2-hydroxy-3-(4-(naphthalen-2yl)piperazin-1-yl)propoxy)-3,4-dihydroquinolin-2(1H)-one

(R)-6-(2-hydroxy-3-(4-p-tolylpiperazin-1-yl)propoxy)-3,4-dihydroquinolin-2(1H)-one

(R)-6-(2-hydroxy-3-(4-phenylpiperazin-1-yl)propoxy)-3,4-dihydroquinolin-2(1H)-one

(R)-6-(3-(4-(4-fluorophenyl)piperazin-1-yl)-2-hydroxypropoxy)-3,4-dihydroquinolin-2(1H)-one

In another embodiment, the compound is selected from Table 8.

TABLE 8 Compound NAME

(S)-6-(3-(4-(3,4-dichlorophenyl)piperazin-1-yl)-2-hydroxypropoxy)quinolin-2(1H)-one

(S)-6-(3-(4-(3,4-difluorophenyl)piperazin-1-yl)-2-hydroxypropoxy)quinolin-2(1H)-one

(R)-6-(3-(4-(3,4-difluorophenyl)piperazin-1-yl)-2-hydroxypropoxy)quinolin-2(1H)-one

(S)-6-(3-(4-(4-fluorophenyl)piperazin-1-yl)-2-hydroxypropoxy)quinolin-2(1H)-one

(S)-6-(3-(4-(3,4-dimethylphenyl)piperazin-1-yl)-2-hydroxypropoxy)quinolin-2(1H)-one

(S)-6-(2-hydroxy-3-(4-p-tolylpiperazin-1- yl)propoxy)quinolin-2(1H)-one

(S)-4-(4-(2-hydroxy-3-(2-oxo-1,2-dihydroquinolin-6-yloxy)propyl)piperazin-1-yl)benzonitrile

(S)-6-(3-(4-(4-bromophenyl)piperazin-1-yl)-2-hydroxypropoxy)quinolin-2(1H)-one

(S)-6-(2-hydroxy-3-(4-(4-hydroxyphenyl)piperazin-1-yl)propoxy)quinolin-2(1H)-one

(S)-6-(2-hydroxy-3-(4-(4-methoxyphenyl)piperazin-1-yl)propoxy)quinolin-2(1H)-one

(S)-6-(2-hydroxy-3-(4-(4- (trifluoromethyl)phenyl)piperazin-1-yl)propoxy)quinolin-2(1H)-one

(S)-6-(3-(4-(biphenyl-4-yl)piperazin-1-yl)-2-hydroxypropoxy)quinolin-2(1H)-one

(S)-6-(3-(4-(2,4-difluorophenyl)piperazin-1-yl)-2-hydroxypropoxy)quinolin-2(1H)-one

(S)-6-(3-(4-(2-fluorophenyl)piperazin-1-yl)-2-hydroxypropoxy)quinolin-2(1H)-one

(S)-6-(3-(4-(2-chlorophenyl)piperazin-1-yl)-2-hydroxypropoxy)quinolin-2(1H)-one

(S)-6-(2-hydroxy-3-(4-o-tolylpiperazin-1- yl)propoxy)quinolin-2(1H)-one

(S)-2-(4-(2-hydroxy-3-(2-oxo-1,2-dihydroquinolin-6-yloxy)propyl)piperazin-1-yl)benzonitrile

(S)-6-(2-hydroxy-3-(4-phenylpiperazin-1- yl)propoxy)quinolin-2(1H)-one

(S)-6-(3-(4-(3-fluorophenyl)piperazin-1-yl)-2-hydroxypropoxy)quinolin-2(1H)-one

(S)-6-(3-(4-(3-chlorophenyl)piperazin-1-yl)-2-hydroxypropoxy)quinolin-2(1H)-one

(S)-6-(2-hydroxy-3-(4-m-tolypiperazin-1- yl)propoxy)quinolin-2(1H)-one

(S)-6-(2-hydroxy-3-(4-(3- (trifluoromethyl)phenyl)piperazin-1-yl)propoxy)quinolin-2(1H)-one

(S)-6-(3-(4-(4-ethylphenyl)piperazin-1-yl)-2-hydroxypropoxy)quinolin-2(1H)-one

(S)-6-(2-hyroxy-3-(4-(4-isoproylphenyl)piperazin-1-yl)propoxy)quinolin-2(1H)-one

(S)-6-(3-(4-(4-cyclopropylphenyl)piperazin-1-yl)-2-hydroxypropoxy)quinolin-2(1H)-one

(S)-6-(2-hydroxy-3-(4-(4-propylphenyl)piperazin-1-yl)propoxy)quinolin-2(1H)-one

(S)-6-(3-(4-(4-butylphenyl)piperazin-1-yl)-2-hydroxypropoxy)quinolin-2(1H)-one

(S)-6-(2-hydroxy-3-(4-(4-isobutylphenyl)piperazin-1-yl)propoxy)quinolin-2(1H)-one

(S)-6-(2-hydroxy-3-(4-(4-(prop-1-ynyl)phenyl)piperazin-1-yl)propoxy)quinolin-2(1H)- one

(S)-6-(2-hydroxy-3-(4-(naphthalen-2-yl)piperazin-1-yl)propoxy)quinolin-2(1H)-one

6-((S)-3-((R)-4-(4-chlorophenyl)-2-methylpiperazin-1-yl)-2-hydroxypropoxy)quinolin-2(1H)-one

6-((S)-3-((S)-4-(4-chlorophenyl)-2-methylpiperazin-1-yl)-2-hydroxypropoxy)quinolin-2(1H)-one

6-((S)-3-((2S,6R)-4-(4-chlorophenyl)-2,6-dimethylpiperazin-1-yl)-2-hydroxypropoxy)quinolin- 2(1H)-one

6((S)-3-((2S,6R)-2,6-dimethyl-4-p-tolylpiperazin-1-yl)-2-hydroxypropoxy)quinolin-2(1H)-one

(R)-6-(3-(4-(4-chlorophenyl)piperazin-1-yl)-2-hydroxypropoxy)quinolin-2(1H)-one

(R)-6-(3-(4-(3,4-dichlorophenyl)piperazin-1-yl)-2-hydroxypropoxy)quinolin-2(1H)-one

(R)-6-(3-(4-(4-ethylphenyl)piperazin-1-yl)-2-hydroxypropoxy)quinolin-2(1H)-one

(R)-6-(2-hydroxy-3-(4-(4-isopropylphenyl)piperazin-1-yl)propoxy)quinolin-2(1H)-one

(R)-6-(3-(4-(4-cyclopropylphenyl)piperazin-1-yl)-2-hydroxypropoxy)quinolin-2(1H)-one

(R)-6-(2-hydroxy-3-(4-(4-propylphenyl)piperazin-1-yl)propoxy)quinolin-2(1H)-one

(R)-6-(3-(4-(4-butylphenyl)piperazin-1-yl)-2-hydroxypropoxy)quinolin-2(1H)-one

(R)-6-(2-hydroxy-3-(4-(4-isobutylphenyl)piperazin-1-yl)propoxy)quinolin-2(1H)-one

(R)-6-(2-hydroxy-3-(4-(4-(prop-1-ynyl)phenyl)piperazin-1-yl)propoxy)quinolin-2(1H)- one

(R)-6-(2-hydroxy-3-(4-(naphthalen-2-yl)piperazin-1-yl)propoxy)quinolin-2(1H)-one

(R)-6-(2-hydroxy-3-(4-p-tolylpiperazin-1-yl) propoxy)quinolin-2(1H)-one

(R)-6-(2-hydroxy-3-(4-phenylpiperazin-1- yl)propoxy)quinolin-2(1H)-one

(R)-6-(3-(4-(fluorophenyl)piperazin-1-yl)-2-hydroxypropoxy)quinolin-2(1H)-one

(S)-6-(3-(4-benzyl-4-hydroxypiperidin-1-yl)-2-hydroxypropoxy)quinolin-2(1H)-one

(R)-6-(3-(4-benzyl-4-hydroxypiperidin-1-yl)-2-hydroxypropoxy)quinolin-2(1H)-one

(S)-6-(2-hydroxy-3-(4-hydroxy-4-phenylpiperidin-1-yl)propoxy)quinolin-2(1H)-one

In another embodiment, the compound is selected from Table 9.

TABLE 9 Compound Name

N-(4-(2-(3-(3,4-dichlorophenyl)-2-oxoimidazolidin-1-yl)ethoxy)phenyl)methanesulfonamide

N-(4-(3-(3-(3,4-dichlorophenyl)-2-oxoimidazolidin-1-yl)propyl)phenyl)methanesulfonamide

(S)-N-(4-(3-(3-(3,4-dichlorophenyl)-2- oxoimidazolidin-1-yl)-2-hydroxypropoxy)phenyl)methanesulfonamide

(S)-N-(4-(3-(3-(4-chlorophenyl)-2-oxoimidazolidin- 1-yl)-2-hydroxypropoxy)phenyl)methanesulfonamide

(S)-1-(4-chlorophenyl)-3-(2-hydroxy-3-(4-hydroxyphenoxy)propyl)imidazolidin-2-one

1-(4-chlorophenyl)-3-(3-(4- hydroxyphenoxy)propyl)imidazolidin-2-one

(S)-1-(4-(3-(3-(4-chlorophenyl)-2-oxoimidazolidin-1-yl)-2-hydroxypropoxy)phenyl)urea

In another embodiment, the compound is selected from Table 10.

TABLE 10 Compound Name

N-(2-(3,4-difluorophenylamino)ethyl)-2-(4-(methylsulfonamido)phenoxy)acetamide

N-(2-(3,4-dichlorophenylamino)ethyl)-2-(4-(methylsulfonamido)phenoxy)acetamide

N-(2-(3,4-dichlorophenylthio)ethyl)-2-(4-(methylsulfonamido)phenoxy)acetamide

N-(2-(3,4-dichlorophenoxy)ethyl)-2-(4-(methylsulfonamido)phenoxy)acetamide

(E)-N-(3-(3,4-dichlorophenyl)allyl)-2-(4-(methylsulfonamido)phenoxy)acetamide

N-(3-(3,4-dichlorophenyl)propyl)-2-(4-(methylsulfonamido)phenoxy)acetamide

N-(2-(3,4-dichlorophenylamino)ethyl)-3-(4-(methylsulfonamido)phenyl)propanamide

N-(2-(3,4-dichlorophenylthio)ethyl)-3-(4-(methylsulfonamido)phenyl)propanamide

N-(2-(3,4-dichlorophenoxy)ethyl)-3-(4-(methylsulfonamido)phenyl)propanamide

(E)-N-(3-(3,4-dichlorophenyl)allyl)-3-(4-(methylsulfonamido)phenyl)propanamide

N-(3-(3,4-dichlorophenyl)propyl)-3-(4-(methylsulfonamido)phenyl)propanamide

N-(4-(3-(4-(3,4-dichlorophenyl)piperazin-1-yl)-3-oxopropyl)phenyl)methanesulfonamide

N-(4-(2-(4-(3,4-dichlorophenyl)piperazin-1-yl)-2-oxoethoxy)phenyl)methanesulfonamide

N-(4-(3-(4-(3,4-dichlorophenyl)-2-oxopiperazin-1-yl)propyl)phenyl)methanesulfonamide

N-(4-(2-(4-(3,4-dichlorophenyl)-2-oxopiperazin-1-yl)ethoxy)phenyl)methanesulfonamide

(S)-N-(4-(3-(4-(4-chlorophenyl)-2-oxopiperazin-1-yl)-2-hydroxypropoxy)phenyl)methanesulfonamide

(S)-N-(4-(3-(4-(3,4-difluorophenyl)-2-oxopiperazin- 1-yl)-2-hydroxypropoxy)phenyl)methanesulfonamide

N-(4-(3-(4-(3,4-difluorophenyl)-2-oxopiperazin-1-yl)propoxy)phenyl)methanesulfonamide

N-(4-(3-(4-(3,4-difluorophenyl)piperazin-1-yl)-3-oxopropyl)phenyl)methanesulfonamide

N-(4-(2-(4-(3,4-difluorophenyl)piperazin-1-yl)-2-oxoethoxy)phenyl)methanesulfonamide

6-(2-(4-3,4-difluorophenyl)piperazin-1-yl)-2-oxoethoxy)benzo[d]oxazol-2(3H)-one

6-(2-(4-(3,4-dichlorophenyl)piperazin-1-yl)-2-oxoethoxy)benzo[d]oxazol-2(3H)-one

6-(2-(4-(4-Chlorophenyl)piperazin-1-yl)-2-oxoethoxy)benzo[d[oxazol-2(3H)-one

5-(2-(4-(3,4-difluorophenyl)piperazin-1-yl)-2- oxoethoxy)indolin-2-one

5-(2-(4-(4-chlorophenyl)piperazin-1-yl)-2- oxoethoxy)indolin-2-one

5-(2-(4-(3,4-dichlorophenyl)piperazin-1-yl)-2- oxoethoxy)indolin-2-one

6-(2-(4-(3,4-dichlorophenyl)piperazin-1-yl)-2-oxoethoxy)-3,4-dihydroquinolin-2(1H)-one

6-(2-(4-(4-chlorophenyl)piperazin-1-yl)-2-oxoethoxy)-3,4-dihydroquinolin-2(1H)-one

6-(2-(4-(3,4-difluorophenyl)piperazin-1-yl)-2-oxoethoxy)-3,4-dihydroquinolin-2(1H)-one

6-(2-(4-(3,4-dichlorophenyl)piperazin-1-yl)-2-oxoethoxy)quinolin-2(1H)-one

6-(2-(4-(4-chlorophenyl)piperazin-1-yl)-2- oxoethoxy)quinolin-2(1H)-one

6-(2-(4-(3,4-difluorophenyl)piperazin-1-yl)-2-oxoethoxy)quinolin-2(1H)-one

6-(3-(4-(3,4-difluorophenyl)piperazin-1-yl)-3-oxopropoxy)benzo[d]oxazol-2(3H)-one

6-(3-(4-(3,4-dichlorophenyl)piperazin-1-yl)-3-oxopropoxy)benzo[d]oxazol-2(3H)-one

6-(3-(4-(4-chlorophenyl)piperazin-1-yl)-3-oxopropoxy)benzo[d]oxazol-2(3H)-one

5-(3-(4-(3,4-difluorophenyl)piperazin-1-yl)-3- oxopropoxy)indolin-2-one

5-(3-(4-(3,4-dichlorophenyl)piperazin-1-yl)-3- oxopropoxy)indolin-2-one

5-(3-(4-(4-chlorophenyl)piperazin-1-yl)-3- oxopropoxy)indolin-2-one

6-(3-(4-(3,4-difluorophenyl)piperazin-1-yl)-3-oxopropoxy)-3,4-dihydroquinolin-2(1H)-one

6-(3-(4-(4-chlorophenyl)piperazin-1-yl)-3-oxopropoxy)-3,4-dihydroquinolin-2(1H)-one

6-(3-(4-(3,4-dichlorophenyl)piperazin-1-yl)-3-oxopropoxy)-3,4-dihydroquinolin-2(1H)-one

6-(3-(4-(3,4-difluorophenyl)piperazin-1-yl)-3-oxopropoxy)quinolin-2(1H)-one

6-(3-(4-(4-chlorophenyl)piperazin-1-yl)-3- oxopropoxy)quinolin-2(1H)-one

6-(3-(4-(3,4-dichlorophenyl)piperazin-1-yl)-3-oxopropoxy)quinolin-2(1H)-one

5-(2-(4-(3,4-dichlorophenyl)-2-oxopiperazin-1- yl)ethoxy)indolin-2-one

5-(2-(4-(4-chlorophenyl)-2-oxopiperazin-1- yl)ethoxy)indolin-2-one

5-(2-(4-3,4-difluorophenyl)-2-oxopiperazin-1- yl)ethoxy)indolin-2-one

5-(3-(4-(3,4-difluorophenyl)-2-oxopiperazin-1- yl)propoxy)indolin-2-one

5-(3-(4-(3,4-dichlorophenyl)-2-oxopiperazin-1- yl)propoxy)indolin-2-one

5-(3-(4-(4-chlorophenyl)-2-oxopiperazin-1- yl)propoxy)indolin-2-one

6-(2-(4-(3,4-dichlorophenyl)-2-oxopiperazin-1-yl)ethoxy)-3,4-dihydroquinolin-2(1H)-one

6-(2-(4-(4-chlorophenyl)-2-oxopiperazin-1-yl)ethoxy)-3,4-dihydroquinolin-2(1H)-one

6-(2-(4-(3,4-difluorophenyl)-2-oxopiperazin-1-yl)ethoxy)-3,4-dihydroquinolin-2(1H)-one

6-(2-(4-(3,4-dichlorophenyl)piperazin-1-yl)-2-oxoethoxy)quinolin-2(1H)-one

6-(2-(4-(4-chlorophenyl)piperazin-1-yl)-2- oxoethoxy)quinolin-2(1H)-one

6-(2-(4-(3,4-difluorophenyl)piperazin-1-yl)-2-oxoethoxy)quinolin-2(1H)-one

N-(2-(3,4-dichlorophenylamino)ethyl)-2-(2-oxo-2,3-dihydrobenzo[d]oxazol-6-yloxy)acetamide

N-(2-(3,4-difluorophenylamino)ethyl)-2-(2-oxo-2,3-dihydrobenzo[d]oxazol-6-yloxy)acetamide

N-(2-(3,4-difluorophenylamino)ethyl-2-(4- hydroxyphenoxy)acetamide

N-(2-(3,4-difluorophenylamino)ethyl)-3-(4- hydroxyphenyl)propanamide

N-(2-(3,4-difluorophenylamino)ethyl)-2-(3-fluoro-4-hydroxyphenoxy)acetamideIn one embodiment, the compound is not

In another embodiment, the compound is not

In one embodiment, the compound has an IC₅₀ value of 600 nM or less. Inone embodiment, the compound has an IC₅₀ value of 600 nM or less at pH6.9 or an ischemic pH. In one embodiment, the compound is selected fromTable 11.

TABLE 11

In one embodiment, the compound has an IC₅₀ value of 600 nM or less atpH 7.6 or a physiological pH. In one embodiment, the compound isselected from Table 12.

TABLE 12

In one embodiment, the compound has a pH boost of 5 or more. In oneembodiment, the compound is selected from Table 13.

TABLE 13

In one embodiment, the compound has an IC₅₀ of 600 nM or less and a pHboost of 5 or more. In a particular embodiment, the compound is

In another embodiment, the compound is

In another embodiment, the compound is,

In another embodiment, the compound is,

In a particular embodiment, the compound is

In another particular embodiment, the compound is

In another embodiment, the compound is,

In another embodiment, the compound is,

In one embodiment, the compound is selected from the group consistingof:

In one embodiment, the compound is selected from the group consistingof:

In one embodiment, the compound is

In one embodiment, the compound is selected from the group consistingof:

In another embodiment, the compound is selected from the groupconsisting of:

Formula II

In one embodiment, compounds, pharmaceutical compositions and methods oftreatment or prophylaxis of neuropathic pain, stroke, traumatic braininjury, epilepsy, and other neurologic events or neurodegenerationresulting from NMDA receptor activation, comprising administering to ahost in need thereof a compound of Formula II, or a pharmaceuticallyacceptable salt, ester, prodrug or derivative thereof are provided:

Formula II

wherein:each G is independently F, Cl, Br, I, C₁-C₄ alkyl, C₁-C₄ alkoxy, C₆-C₁₂aralkyl, —O-aryl, —S-aryl, —NH-aryl;f=0, 1, 2, 3, 4 or 5;Ar^(a) and Ar^(b) are each independently aryl or heteroaryl;B is selected from the group consisting of:

wherein R^(a), R^(b), R^(c), R^(d), R^(e), R^(f), R^(g), R^(h), R^(k)and R^(p) are each independently selected from H, C₁-C₆ alkyl, C₁-C₆alkoxy, OH or halo;R^(j) is H, C₁-C₆ alkyl, OH or P(O)(OC₁-C₄ alkyl)₂;R_(m) is C₁-C₄ alkyl or C₂-C₄ alkenyl;R^(n) is C₁-C₄ alkyl, C₂-C₄ alkenyl, C₆-C₁₂ aralkyl, —CH₂O—, —CH(C₁-C₆alkyl)O—, —CH(C₂-C₁₂ aralkyl)O—;t, w, y and z each=0, 1, 2, or 3;X and X′ are independently selected from a bond, O, S, SO, SO₂, CH₂, NH,N(C₁-C₆ alkyl), and NHC(═O);M is OH, F, Cl, Br, I, NH₂, NR^(q)R^(r), NO₂, O(C₁-C₆ alkyl), OCF₃, CN,C(O)OH, C(O)O(C₁-C₆ alkyl), C₆-C₁₂ aralkyl, NR^(s)C(O)CR^(t) ₃, orNR^(u)C(O)NR^(v) ₂, wherein each R^(q), R^(r), R^(s), R^(u) and R^(v) iseach independently H or C₁-C₆ alkyl; and each R^(t) is independently H,C₁-C₆ alkyl or halo; or two M groups may be taken together with Ar^(b)to form:

and wherein R^(a) and R^(w) are independently H, C₁-C₆ alkyl or C₆-C₁₂aralkyl; andh=1, 2, 3, 4 or 5;wherein when B contains a piperidin-4-ol or a pyrrolidin-2-ol moiety,and Ar^(a) and Ar^(b) are each phenyl, M is not OH at the para positionon Ar^(b).

In one embodiment, G is F or Cl. In another embodiment, f is 1 or 2.

In one embodiment, Ar^(a) is phenyl. In another embodiment, Ar^(b) isphenyl. In another embodiment, Ar^(a) and Ar^(b) are each phenyl.

In one embodiment, Ar^(a) is phenyl and is substituted with two Ggroups. In a subembodiment, both G groups are Cl. In anothersubembodiment, both G groups are F. In another subembodiment, one Ggroup is Cl and the other G group is F. In one embodiment, G is selectedfrom the group consisting of C₆-C₁₂ aralkyl, —O-aryl, —S-aryl, and—NH-aryl.

In one embodiment, B is

In a subembodiment, R^(a), R^(b), R^(c), R^(d), R^(e), R^(g) and R^(h)are H; Rj is H, C₁-C₆ alkyl, OH or P(O)(OC₁-C₄ alkyl)₂; R^(f) is H, haloor OH; t is 0, 1, 2, or 3; and w, y and z are each 1.

In one embodiment, B is

In a subembodiment, R^(a), R^(b), R^(c), R^(d), R^(e), R^(g) and R^(h)are H; R^(f) is H, halo or OH; R^(k) is H, halo or OH; R^(m) is C₁-C₄alkyl; t is 1, 2, or 3; and w, y and z are each 1.

In one embodiment, B is

In a subembodiment, R^(a), R^(b), R^(c), R^(d), R^(e), R^(g) and R^(h)are H; R^(f) is H, halo or OH; R^(p) is H, halo or OH; R^(n) is —CH₂O—;t is 0, 1, 2, or 3; and w, y and z are each 1.

In one embodiment, the sum of w, y and z does not exceed 6. In oneembodiment, the sum of w, y and z is 2, 3, 4, 5 or 6.

In one embodiment, X is a bond, O, S or CH₂. In another embodiment, X isO. In another embodiment, X is CH₂.

In one embodiment, X′ is a bond, NH, S or CH₂. In another embodiment, X′is a bond. In another embodiment, X′ is S. In another embodiment, X′ isNH. In another embodiment, X′ is CH₂.

In one embodiment, M is OH. In another embodiment, M is F or Cl. Inanother embodiment, M is O(C₁-C₆ alkyl), for example OCH₃, OCH₂CH₃,O(CH₂)₂CH₃, OCH(CH₃)₂ or OC(CH₃)₃. In another embodiment, M is NH₂. Inanother embodiment, M is NR^(q)R^(r). In another embodiment, M is NO₂.In another embodiment, M is OCF₃. In one embodiment, M is CN. In oneembodiment, M is C(O)OH. In one embodiment, M is C(O)O(C₁-C₆ alkyl), forexample C(O)OCH₃, C(O)OCH₂CH₃, C(O)O(CH₂)₂CH₃, C(O)OCH(CH₃)₂ orC(O)OC(CH₃)₃. In one embodiment, M is C₆-C₁₂ aralkyl, for exampleCH₂-phenyl. In one embodiment, M is NR^(s)C(O)CR^(t) ₃. In asubembodiment, R^(s) is H. In a subembodiment, R^(t) is H or Cl. In oneembodiment, M is NR^(u)C(O)NR^(v) ₂, for example, NHC(O)NH₂. In asubembodiment, R^(u) is H and R^(v) is H or alkyl.

In one embodiment, two M groups may be taken together with Ar^(b) toform:

In a subembodiment, two M groups may be taken together with Ar^(b) toform:

In one embodiment, R^(u) and R^(w) are both H. In one embodiment, h is 1or 2.

In one embodiment, the compound is a compound of Formula II, or apharmaceutically acceptable salt, ester, prodrug or derivative thereof,wherein:

each G is independently F, Cl, Br or I;f is 0, 1, 2, 3, 4, or 5;Ar^(a) and Ar^(b) are each independently selected from the groupconsisting of phenyl, pyridyl, pyrimidinyl, thiophenyl, imidazolyl,furanyl, indolyl, benzothiophenyl, benzofuranyl, benzoimidazolyl;B is selected from the group consisting of:

wherein R^(a), R^(b), R^(c), R^(d), R^(e), R^(f), R^(g), R^(h), R^(k)and R^(p) are each independently selected from H, C₁-C₆ alkyl, OH, orhalo;R^(j) is H, C₁-C₆ alkyl, C₇-C₁₂ aralkyl, or OH;R^(m) is C₁-C₄ alkyl or C₂-C₄ alkenyl;R^(n) is C₁-C₄ alkyl, C₂-C₄ alkenyl, C₆-C₁₂ aralkyl, —CH₂O—, —CH(C₁-C₆alkyl)O—, —CH(C₂-C₁₂ aralkyl)O—;t, w, y and z each=0, 1, 2, or 3;X is a bond, CH₂ or O;X′ is a bond, CH₂, S or NH;M is OH, F, Cl, Br, I, NH₂, NR^(q)R^(r), NO₂, O(C₁-C₆ alkyl), OCF₃, CN,C(O)OH, C(O)O(C₁-C₆ alkyl), C₆-C₁₂ aralkyl, NR^(s)C(O)CR^(t) ₃, orNR^(u)C(O)NR^(v) ₂; wherein each R^(q), R^(r), R^(s), R^(u) and R^(v) iseach independently H or C₁-C₆ alkyl; and each R^(t) is independently H,C₁-C₆ alkyl or halo; or two M groups may be taken together with Ar^(b)to form:

and wherein R^(u) and R^(w) are independently H or C₁-C₄ alkyl; andh=1, 2 or 3.

In one embodiment, the compound is a compound of Formula II, or apharmaceutically acceptable salt, ester, prodrug or derivative thereof,wherein:

each G is independently F, Cl, Br or I;f=0, 1, 2, 3, 4 or 5;Ar^(a) and Ar^(b) are each phenyl;B is selected from the group consisting of:

wherein R^(a), R^(b), R^(c), R^(d), R^(e), R^(f), R^(g), R^(h), R^(k)and R^(p) are each independently selected from H, C₁-C₆ alkyl, OH, orhalo;R^(j) is H, C₁-C₆ alkyl, or OH;R^(m) is C₁-C₄ alkyl or C₂-C₄ alkenyl;R^(n) is C₁-C₄ alkyl, C₂-C₄ alkenyl, C₆-C₁₂ aralkyl, —CH₂O—, —CH(C₁-C₆alkyl)O—, —CH(C₂-C₁₂ aralkyl)O—;t, w, y and z each=0, 1, 2, or 3;X is a bond, CH₂ or O;X′ is a bond, CH₂, S or NH;M is OH, F, Cl, Br, I, NH₂, NR^(q)R^(r), NO₂, O(C₁-C₆ alkyl), OCF₃, CN,C(O)OH, C(O)O(C₁-C₆ alkyl), C₆-C₁₂ aralkyl, NR^(s)C(O)CR^(t) ₃; whereineach R^(q), R^(r), and R^(s) is each independently H or C₁-C₆ alkyl; andeach R^(t) is independently H, C₁-C₆ alkyl or halo; or two M groups maybe taken together with Ar^(b) to form:

and wherein R^(u) is H or C₁-C₄ alkyl; andh=1, 2 or 3.

In one embodiment, M is NR^(u)C(O)NR^(v) ₂, for example NHC(O)NH₂ orNHC(O)N(CH₃)₂.

In another embodiment, Ar^(b)-M is selected from the group consistingof:

In one embodiment, the compound is

or6-{3-[2-(3,4-Dichloro-phenyl)-ethylamino]-2-(S)-hydroxy-propoxy}-3H-benzooxazol-2-one.

In one embodiment, the compound is

In one embodiment, the compound is selected from the compounds in Table14.

TABLE 14 Compound NAME

4-{3-[2-(3,4-Dichloro-phenyl)-ethylamino]-2-(S)- hydroxy-propoxy}-phenol

4-(3-{Butyl-[2-(3,4-dichloro-phenyl)-ethyl]-amino}-2-(S)-hydroxy-propoxy)-phenol

4-{3-[2-(3,4-Dichloro-phenyl)-ethylamino]-2-(S)-hydroxy-propoxy}-3-fluoro-phenol

4-{3-[2-(3,4-Dichloro-phenyl)-ethylamino]-2-(S)-hydroxy-propoxy}-2-fluoro-phenol

1-[2-(S)-Hydroxy-3-(4-hydroxy-phenoxy)-propyl]- 4-phenyl-piperidin-4-ol

(R)-1-(4-(2-hydroxy-3-(4-hydroxy-4-phenylpiperidin-1-yl)propoxy)phenyl)urea

(S)-1-(4-(2-hydroxy-3-(4-hydroxy-4-phenylpiperidin-1-yl)propoxy)phenyl)urea

(S)-1-(4-(3-(4-benzyl-4-hydroxypiperidin-1-yl)-2-hydroxypropoxy)phenyl)urea

(R)-1-(4-(3-(4-benzyl-4-hydroxypiperidin-1-yl)-2-hydroxypropoxy)phenyl)urea

1-(4-(3-(4-benzyl-4-hydroxypiperidin-1-yl)-2- hydroxypropoxy)phenyl)urea

1-(4-(3-(4-(4-chlorobenzyl)-4-hydroxypiperidin-1-yl)-2-hydroxypropoxy)phenyl)urea

1-(4-(2-hydroxy-3-(4-hydroxy-4-phenylpiperidin-1- yl)propoxy)phenyl)urea

(S)-5-(3-(4-benzyl-4-hydroxypiperidin-1-yl)-2-hydroxypropoxy)indolin-2-one

(R)-5-(3-(4-benzyl-4-hydroxypiperidin-1-yl)-2-hydroxypropoxy)indolin-2-one

(S)-5-(2-hydroxy-3-(4-hydroxy-4-phenylpiperidin-1-yl)propoxy)indolin-2-one

(R)-5-(2-hydroxy-3-(4-hydroxy-4-phenylpiperidin-1-yl)propoxy)indolin-2-one

(R)-6-(3-(4-benzyl-4-hydroxypiperidin-1-yl)-2-hydroxypropoxy)-3,4-dihydroquinolin-2(1H)-one

(S)-6-(3-(4-benzyl-4-hydroxypiperidin-1-yl)-2-hydroxypropoxy)-3,4-dihydroquinolin-2(1H)-one

(S)-6-(2-hydroxy-3-(4-hydroxy-4-phenylpiperidin-1-yl)propoxy)-3,4-dihydroquinolin-2(1H)-one

(R)-6-(2-hydroxy-3-(4-hydroxy-4-phenylpiperidin-1-yl)propoxy)-3,4-dihydroquinolin-2(1H)-one

(R)-6-(2-hydroxy-3-(4-hydroxy-4-phenylpiperidin-1-yl)propoxy)quinolin-2(1H)-one

In one embodiment, the compound has an IC₅₀ value of 600 nM or less. Inone embodiment, the compound has an IC₅₀ value of 600 nM or less at pH6.9 or an ischemic pH. In one embodiment, the compound is selected fromTable 15.

TABLE 15

In one embodiment, the compound has a pH boost of 5 or more. In oneembodiment, the compound is

In one embodiment, the compound is selected from the group consistingof:

In one embodiment, the compound is

In another embodiment, the compound is selected from the groupconsisting of:

In another embodiment the compound is

In one embodiment, one or more of R^(c), R^(d), R^(e), R^(f), R^(g), andR^(h) is an OH group which creates a stereogenic center. In a particularsubembodiment, one of R^(c), R^(d), R^(e), R^(f), R^(g) and R^(h) is anOH group which creates a stereogenic center. In another subembodiment,the OH group at one of R^(c), R^(d), R^(e), R^(f), R^(g), and R^(h) isin the R configuration. In another subembodiment, the OH group at one ofR^(c), R^(d), R^(e), R^(f), R^(g), and R^(h) is in the S configuration.

In certain embodiments, the binding to both hERG and alpha-1 adrenergicreceptors can be modulated by changing the G substituent or Gsubstituents. In particular, for compounds wherein Ar^(a) is phenyl, thebinding to both hERG and alpha-1 adrenergic receptors can be modulatedby changing the substitution at the 3 and/or 4 positions. In oneembodiment, the Ar^(a) phenyl is substituted at the 3 and/or 4 positionwith, for example, fluorine or chlorine. In certain embodiments,substitution at the 3 and/or 4 positions of the Ar^(a) phenyl canincrease potency.

In certain embodiments, both hERG and alpha-1 adrenergic binding can bereduced by substituting N at the R^(j) position with C₂-C₁₂ aralkyl. Ina particular subembodiment, R^(j) is benzyl.

In certain embodiments, alpha-1 adrenergic binding is reduced when R^(j)is C₁-C₆ alkyl.

When Ar^(b) is phenyl, para substitution of the M substituent isparticularly preferred. Additional M substitutents on the Ar^(b) phenylare preferred at one or more ortho positions. Additional substitution onthe Ar^(b) phenyl at one or more meta positions can reduce potency.

In certain embodiments, the Ar^(a) phenyl is not substituted by twofluoro groups. In one embodiment, the Ar^(a) phenyl is not substitutedby two methyl groups. In one embodiment, the Ar^(a) phenyl is notsubstituted by one halo group. In one embodiment, the Ar^(a) phenyl isnot substituted by one fluoro or alkyl group at the C-2 position. In oneembodiment, the Ar^(a) phenyl is not substituted by a OH or NO₂ group.

In one embodiment, when Ar^(a) and Ar^(b) are both phenyl, at least oneof for h is not 0.

In one embodiment, when Ar^(a) and Ar^(b) are both phenyl, f is not 0.In one embodiment, when Ar^(a) and Ar^(b) are both phenyl, h is not 0.In one embodiment, when Ar^(a) and Ar^(b) are both phenyl, X is not CH₂.In one embodiment, when Ar^(a) and Ar^(b) are both phenyl, X′ is notCH₂. In another embodiment, M is not OH. In one embodiment, the compoundis not

In one embodiment, M is not aralkoxy. In one embodiment, the compound isnot

In one embodiment, B does not contain a piperidinyl moiety. In anotherembodiment, when B contains a piperidinyl moiety, and Ar^(a) and Ar^(b)are both phenyl, M is not OH. In one embodiment, when B contains apiperidinyl moiety, M is NR^(u)C(O)NR^(v) ₂, for example, NHC(O)NH₂. Ina subembodiment, R^(u) is H and R^(v) is H or alkyl. In one embodiment,when B contains a piperidinyl moiety, X is not CH₂. In one embodiment,when B contains a piperidinyl moiety, X′ is not CH₂. In one embodiment,R^(k) is not OH. In one embodiment, R^(P) is not OH.

In one embodiment, when B contains a hydroxy-substituted-piperidinylmoiety, X is not CH₂. In one embodiment, when B contains ahydroxy-substituted-piperidinyl moiety, X′ is not CH₂. In oneembodiment, B does not contain a hydroxy-substituted-piperidinyl moiety.

In one embodiment, X is not SO₂. In another embodiment, X′ is not SO₂.In one embodiment, when B contains a piperidinyl moiety, X is not SO₂.In one embodiment, when B contains a piperidinyl moiety, X′ is not SO₂.

In one embodiment, X is not S. In another embodiment, X′ is not S. Inone embodiment, when B contains a piperidinyl moiety, X is not S. In oneembodiment, when B contains a piperidinyl moiety, X′ is not S.

In another embodiment, M is not OCH₃ or OCF₃. In another embodiment, Mis not NO₂. In one embodiment, when B contains a nitrogen-containingheterocycle, Ar^(b)—X is not heteroaryl-NH. In another embodiment, whenB contains a nitrogen-containing heterocycle, Ar^(a)—X′ is notheteroaryl-NH.

In one embodiment, when B contains a nitrogen-containing heterocycle, Xis not NH(C═O). In another embodiment, when B contains anitrogen-containing heterocycle, X′ is not NH(C═O).

Formula III

In one embodiment, compounds, pharmaceutical compositions and methods oftreatment or prophylaxis of neuropathic pain, stroke, traumatic braininjury, epilepsy, and other neurologic events or neurodegenerationresulting from NMDA receptor activation, comprising administering to ahost in need thereof a compound of Formula III, or a pharmaceuticallyacceptable salt, ester, prodrug or derivative thereof are provided:

wherein:Z* is OH, NR^(10*)R^(11*), NR^(12*)SO₂R^(11*),NR^(12*)C(O)NR^(10*)R^(11*), NR^(12*)C(O)OR^(10*),NR^(12*)-dihydrothiazole, or NR^(12*)-dihydroimidazole; wherein eachR^(10*), R^(11*) and R^(12*) is independently H, C₁-C₆ alkyl or C₆-C₁₂aralkyl; or

Ar^(1*) and Ar^(2*) are each independently aryl or heteroaryl;R^(1*), R^(2*), R^(4*), R^(5*), R^(7*), R^(8*) are independently H, OHor C₁-C₄ alkyl;n*=1, 2, 3 or 4;p*=0, 1, 2 or 3;q*=0, 1 or 2;R^(3*) and R^(6*) are each independently H or C₁-C₄ alkyl;X^(1*) and X^(2*) are each independently O, S, N(C₁-C₄ alkyl) or C(H orC₁-C₄ alkyl)₂;W* is NR^(9*) or CR^(13*)R^(14*); wherein R^(9*), R^(13*) and R^(14*)are each independently is H or C₁-C₄ alkyl;each L* is independently C₁-C₆ alkyl, C₁-C₆ alkoxy, C(═O)—(C₁-C₆)-alkyl,C₁-C₆ haloalkyl, hydroxy, fluoro, chloro, bromo, iodo, nitro, or cyano;or two L groups may be taken together with Ar^(2*) to form a dioxolanering or a cyclobutane ring;k*=0, 1, 2, 3, 4 or 5;or

In one embodiment, Z* is OH, NR^(12*)SO₂R^(11*); wherein R^(12*) is H orC₁-C₄ alkyl, and R^(11*) is C₁-C₄ alkyl or C₂-C₁₀ aralkyl. In oneembodiment, Z* is OH. In another embodiment, Z* is NR^(12*)SO₂R^(11*),for example, NHSO₂CH₃.

In one embodiment, Z* is NR^(12*)C(O)NR^(10*)R^(11*) or

In one embodiment, Ar^(1*) and Ar^(2*) are each phenyl.

In one embodiment, R^(1*), R^(2*), R^(4*), R^(5*), R^(7*), R^(8*) are H.

In a particular embodiment, n* is 2.

In one embodiment, p* is 0, 1 or 2. In another embodiment, p* is 0. Inanother embodiment, p* is 1. In another embodiment, p* is 2.

In one embodiment, q* is 0. In another embodiment, q* is 1. In anotherembodiment, q* is 2.

In one embodiment, R^(3*) and R^(6*) are both H. In one embodiment,R^(6*) is C₁-C₄ alkyl, for example methyl, ethyl, propyl, isopropyl,n-butyl, sec-butyl, or tert-butyl.

In one embodiment, X* is S. In one embodiment, X* is O.

In one embodiment, W* is NR^(7*), for example NH. In another embodiment,W* is CR^(13*)R^(14*), for example CH₂.

In one embodiment, each L* is independently selected from C₁-C₄ alkyl,F, Cl, Br, I, or C₁-C₄ haloalkyl, for example, Cl, CH₃ or CF₃. In oneembodiment, k* is 1. In another embodiment, k* is 2.

In one embodiment, the compound is a compound of Formula III, or apharmaceutically acceptable salt, ester, prodrug or derivative thereof,wherein:

Z* is OH, NHSO₂CH₃;

Ar^(1*) is phenyl;R^(1*), R^(2*), R^(4*), R^(5*) are independently H or C₁-C₄ alkyl;n*=2;p*=0, 1 or 2;q*=0, 1 or 2;R^(3*) and R^(6*) are each independently H or C₁-C₄ alkyl;

X* is O or S;

W* is NR^(7*) or CR^(13*)R^(14*); wherein R^(7*), R^(13*) and R^(14*)are each independently is H or C₁-C₄ alkyl;Ar^(2*) is phenyl;each L* is independently selected from C₁-C₄ alkyl, F, Cl, Br, I, C₁-C₄haloalkyl;k*=0, 1, 2, 3, 4 or 5;or

In one embodiment, the compound is selected from the group consistingof:

In another embodiment, the compound is selected from the groupconsisting of:

In one embodiment, compounds, pharmaceutical compositions and methods oftreatment or prophylaxis of neuropathic pain, stroke, traumatic braininjury, epilepsy, and other neurologic events or neurodegenerationresulting from NMDA receptor activation, comprising administering to ahost in need thereof a compound of Formula IV, or a pharmaceuticallyacceptable salt, ester, prodrug or derivative thereof are provided:

(L**)_(k**)-AR^(1**)—X**—(CR^(1**)R^(2**))_(n**)—Y**—AR^(2**)—Z**  FORMULAIV

wherein:each L** is independently C₁-C₆ alkyl, C₁-C₆ alkoxy,C(═O)—(C₁-C₆)-alkyl, C₁-C₆ haloalkyl, hydroxy, fluoro, chloro, bromo,iodo, nitro, or cyano; or two L** groups may be taken together withAr^(1**) to form: a dioxolane ring or a cyclobutane ring;k**=0, 1, 2, 3, 4 or 5;each Ar^(1**) and Ar^(2**) is independently aryl or heteroaryl;X** is S, O or NR³; wherein R³ is H, C₁-C₆ alkyl, or C₆-C₁₂ aralkyl;each R^(1**) and R^(2**) is independently H, C₁-C₆ alkyl, C₁-C₆ alkoxy,C₆-C₁₂ aralkyl, C(═O)—(C₁-C₆)-alkyl, C₁-C₆ haloalkyl, hydroxy, fluoro,chloro, bromo, iodo, nitro, or cyano; or CR¹R² can be C═O or C═CH₂;n**=1, 2, 3 or 4;Y** is a bond, O, S, SO, SO₂, CH₂, NH, N(C₁-C₆ alkyl), or NHC(═O);Z** is OH, NR^(6**)R^(7**), NR^(8**)SO₂(C₁-C₆ alkyl),NR^(8**)C(O)NR^(6**)R^(7**), NR^(8**)C(O)O(C₁-C₆ alkyl),NR^(8**)-dihydrothiazole, or NR^(8**)-dihydroimidazole; wherein eachR^(6**), R^(7**) and R^(8**) is independently H, C₁-C₆ alkyl or C₆-C₁₂aralkyl; or

wherein R^(9**) and R^(10**) are each independently H, C₁-C₆ alkyl,aralkyl.

In particular subembodiment, Ar^(1**) is phenyl, pyridyl, pyrimidinyl,thiophenyl, imidazolyl, furanyl, indolyl, benzothiophenyl, benzofuranyl,or benzoimidazolyl. In one embodiment, Ar^(2**) is phenyl. In anotherembodiment, Ar^(1**) is benzoimidazolyl. In a particular subembodiment,Ar^(2**) is phenyl and Ar^(1**) is a heteroaryl, for examplebenzoimidazolyl. In one embodiment, Ar^(1**) is a bicyclic group whereinthe X^(**) group is attached to the heterocyclic ring.

In one embodiment, X** is S. In one embodiment, X** is O. In oneembodiment, X** is NR^(3**), for example NH.

In another particular subembodiment, L** is C₁-C₄ alkyl, C₁-C₄ alkoxy,C(═O)—(C₁-C₄)-alkyl, C₁-C₆ haloalkyl, hydroxy, fluoro, chloro, bromo,iodo, nitro, or cyano. In a further subembodiment, L** is methyl,trifluoromethyl, methoxy, nitro, fluoro, chloro or hydroxy. In onefurther subembodiment, there are one, two or three L** groupssubstituting Ar^(1**). In one subembodiment, Ar^(1**) is substitutedwith one fluoro group. In one subembodiment, Ar^(1**) is substitutedwith two fluoro groups. In one subembodiment, Ar^(1**) is substitutedwith one fluoro group and one chloro group. In one subembodiment,Ar^(1**) is substituted with one chloro group. In one subembodiment,Ar^(1**) is substituted with two chloro groups. In one subembodiment,Ar^(1**) is substituted with one methyl group. In one subembodiment,Ar^(1**) is substituted with one trifluoromethyl group.

In one embodiment, each R^(1**) and R^(2**) is independently H or C₁-C₄alkyl, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl,sec-butyl or tert-butyl. In one embodiment, R^(1**) and R^(2**) are bothH. In one embodiment, one R^(1**) or R^(2**) is hydroxy. In oneembodiment, n** is 2, 3, or 4. In one embodiment, n** is 3.

In one embodiment, one CR^(1**)R^(2**) is C═O or C═CH₂. In oneembodiment, (CR^(1**)R^(2**))_(n**) is selected from the groupconsisting of

In an particular embodiment, (CR^(1**)R^(2**))_(n**) is

In one embodiment, Y** is a bond, O or CH₂. In one embodiment, Y** is O.In one subembodiment, Ar^(2**) is phenyl and is substituted with a Z**group at the 4 position.

In one embodiment, Z** is OH, NR^(6**)R^(7**), NR^(8**)SO₂(C₁-C₆ alkyl),NR^(8**)C(O)NR^(6**)R^(7**), NR^(8**)C(O)O(C₁-C₆ alkyl),NR^(8**)-dihydrothiazole, or NR^(8**)-dihydroimidazole. In onesubembodiment, Ar^(2**) is phenyl and is substituted with a Z group atthe 4 position. In one embodiment,

In one embodiment,

In one subembodiment,

In one subembodiment, R^(9**) and R^(10**) are each H.

In another subembodiment, Z** is NR^(8**)C(O)NR^(6**)R^(7**) or

In one embodiment, the compound is a compound of Formula IV, or apharmaceutically acceptable salt, ester, prodrug or derivative thereof,wherein:

L** is C₁-C₄ alkyl, C₁-C₄ alkoxy, C(═O)—(C₁-C₄)-alkyl, C₁-C₄ haloalkyl,hydroxy, fluoro, chloro, bromo, iodo, or nitro;k**=0, 1, 2, 3, 4 or 5;Ar^(1**) is selected from the group consisting of phenyl, pyridyl,pyrimidinyl, thiophenyl, imidazolyl, furanyl, indolyl, benzothiophenyl,benzofuranyl, or benzoimidazolyl.;Ar^(2**) is phenyl;

X** is S;

each R^(1**) and R^(2**) is independently H, hydroxy or C₁-C₄ alkyl; orCR^(1**)R^(2**) is C═O;n**=2, 3 or 4;

Y** is O;

Z** is OH, NH₂, NHSO₂(C₁-C₄ alkyl), NHC(O)NR^(6**)R^(7**), NHC(O)O(C₁-C₄alkyl), NH-dihydrothiazole, or NH-dihydroimidazole; wherein each R^(6**)and R^(7**) is independently H or C₁-C₄ alkyl; or

R^(9**) is H or C₁-C₄ alkyl.

In one embodiment, the compound is selected from the group consistingof:

In one embodiment, the compound is

In one embodiment, the compound is selected from the group consistingof:

In one embodiment, the compound is

In another embodiment, the compound is selected from the groupconsisting of:

In another embodiment, the compound is selected from Table 16.

TABLE 16 Compound Name

(R)-4-(3-(5,6-dichloro-1H- benzo[d]imidazol-2-ylthio)-2-hydroxypropoxy)phenol

(R)-5-(3-(5,6-dichloro-1H- benzo[d]imidazol-2-ylthio)-2-hydroxypropoxy)indolin-2-one

(R)-6-(3-(5,6-dichloro-1H- benzo[d]imidazol-2-ylthio)-2-hydroxypropoxy)-3,4- dihydroquinolin-2(1H)-one

(R)-6-(3-(5,6-dichloro-1H- benzo[d]imidazol-2-ylthio)-2-hydroxypropoxy)quinolin-2(1H)-one

(R)-1-(4-(3-(5,6-dichloro-1H- benzo[d]imidazol-2-ylthio)-2-hydroxypropoxy)phenyl)urea

(R)-N-(4-(3-(5,6-dichloro-1H- benzo[d]imidazol-2-ylthio)-2-hydroxypropoxy)phenyl) methanesulfonamide

(R)-N-(4-(2-hydroxy-3-(6-methyl-1H- benzo[d]imidazol-2-ylthio)propoxy)phenyl) methanesulfonamide

Formula V

In one embodiment, compounds, pharmaceutical compositions and methods oftreatment or prophylaxis of neuropathic pain, stroke, traumatic braininjury, epilepsy, and other neurologic events or neurodegenerationresulting from NMDA receptor activation, comprising administering to ahost in need thereof a compound of Formula V, or a pharmaceuticallyacceptable salt, ester, prodrug or derivative thereof are provided:

Ar′—W′—B′—W″—Y′—Ar″—Z′  FORMULA V

wherein B′ is selected from the group consisting of:

W′ is a bond or C₁-C₄ alkyl;W″ is C₁-C₄ alkyl, C₁-C₄ hydroxyalkyl, C₁-C₄ haloalkyl or C(═O)—C₁-C₄alkyl;Y′ is selected from a bond, O, S, CH₂ and N;Ar′ is an substituted or unsubstituted aromatic or nonaromaticcycloalkyl which optionally may include 0-3 heteroatoms;Ar″ is an aromatic or nonaromatic cycloalkyl which optionally mayinclude 0-3 heteroatoms;Z′ is NRC(O)NR₂ wherein each R is independently selected from H, C₁-C₆alkyl or C₆-C₁₂ aralkyl; orAr″—Z′ are taken together and selected from the group consisting of:

In one embodiment, Ar′ is substituted by (L′)_(k)′ wherein each L′ isindependently C₁-C₆ alkyl, C₁-C₆ alkoxy, C(═O)—(C₁-C₆)-alkyl, C₁-C₆haloalkyl, alkaryl, hydroxy, —O-alkyl, —O-aryl, —SH, —S-alkyl, —S-aryl,fluoro, chloro, bromo, iodo, nitro, or cyano; or two L′ groups may betaken together with Ar′ to form a dioxolane ring or a cyclobutane ring;and k′=1, 2, 3, 4 or 5.

In one embodiment B′ is

In another embodiment, B′ is

In another embodiment, B′ is

In another embodiment, B′ is

In another embodiment, B′ is

In one embodiment, W′ is a bond. In another embodiment, W′ is C₁-C₄alkyl, for example methylene, ethylene, or propylene. In a particularsubembodiment, W′ is CH₂.

In one embodiment W″ is C₁-C₄ alkyl, for example methylene, ethylene,propylene, methylpropylene, or butylene. In another embodiment, W″ isC₁-C₄ hydroxyalkyl, for example hydroxymethylene, hydroxyethylene, orhydroxypropylene. In a particular subembodiment, W″ is —CH₂,CH(OH)—CH₂—. In another embodiment, W″ is C₁-C₄ haloalkyl, for examplefluoroethylene, fluoropropylene, chloroethylene, or chloropropylene.

In another embodiment, W″ is C(═O)—C₁-C₄ alkyl, for example —C(═O)—CH₂—or —C(═O)—CH₂—CH₂—.

In one embodiment, Ar′ is an aromatic cycloalkyl, for example phenyl. Inanother embodiment, Ar′ is an nonaromatic cycloalkyl, for examplecyclopentyl or cyclohexyl. In another embodiment, Ar′ is an aromaticcycloalkyl including 1-3 heteroatoms, for example pyrrole, furan,thiophene, pyridine, pyrimidine, pyrazine, pyridazine. Heteroatomsinclude but are not limited to N, S and O. In another embodiment, Ar′ isa nonaromatic cycloalkyl including 1-3 heteroatoms, for examplepyrrolidine, pyrroline, dihydrofuran, tetrahydrofuran, dihydrothiophene,tetrahydrothiophene, piperidine, tetrahydropyran, pyran, thiane,thiiine, piperazine, oxazine, dithiane, or dioxane. In anotherembodiment, Ar′ is an aromatic or nonaromatic cycloalkyl including 1heteroatom. In another embodiment, Ar′ is an aromatic or nonaromaticcycloalkyl including 2 heteroatoms. In another embodiment, Ar′ is anaromatic or nonaromatic cycloalkyl including 3 heteroatoms.

In one embodiment, Ar″ is an aromatic cycloalkyl, for example phenyl. Inanother embodiment, Ar″ is an nonaromatic cycloalkyl, for examplecyclopentyl or cyclohexyl. In another embodiment, Ar″ is an aromaticcycloalkyl including 1-3 heteroatoms, for example pyrrole, furan,thiophene, pyridine, pyrimidine, pyrazine, or pyridazine. In anotherembodiment, Ar″ is a nonaromatic cycloalkyl including 1-3 heteroatoms,for example pyrrolidine, pyrroline, dihydrofuran, tetrahydrofuran,dihydrothiophene, tetrahydrothiophene, piperidine, tetrahydropyran,pyran, thiane, thiiine, piperazine, oxazine, dithiane, or dioxane.

In another embodiment, Ar″ is an aromatic or nonaromatic cycloalkylincluding 1 heteroatom. In another embodiment, Ar″ is an aromatic ornonaromatic cycloalkyl including 2 heteroatoms. In another embodiment,Ar″ is an aromatic or nonaromatic cycloalkyl including 3 heteroatoms.

In one embodiment, Z′ is NRC(O)NR₂, for example NHC(O)NH₂ orNHC(O)N(CH₃)₂.

In another embodiment, Z and Ar″ are taken together and selected fromthe group consisting of:

In a particular subembodiment, Ar″—Z′ is

In another subembodiment, Ar″—Z′ is

In another subembodiment, Ar″—Z′ is

In another subembodiment, Ar″—Z′ is

In another subembodiment, Ar″—Z′ is

In another subembodiment, Ar″—Z′ is

In a particular subembodiment of any of the above embodiments, R is H.In a particular subembodiment of any of the above embodiments, Ar″ isphenyl.

In one embodiment, each L′ is independently halo, C₁-C₆ alkyl, or C₁-C₆haloalkyl. In a particular subembodiment Ar′ has at least one L′. In aparticular subembodiment Ar′ is phenyl and is substituted with one ormore L′ groups wherein one L′ is in the para position. In a particularembodiment, at least one L′ is halo, for example fluoro, chloro, bromo,or iodo. In a particular subembodiment, are least two L′ are halo andmay be the same or different. In another embodiment, at least one L′ isC₁-C₆ alkyl, for example methyl, ethyl, propyl, isopropyl, butyl,isobutyl, pentyl, or hexyl. In another embodiment, at least one L′ isC₁-C₆ haloalkyl, for example, trifluoromethyl.

In one embodiment, Ar′ is unsubstituted. In another embodiment, k′ is 1.In a subembodiment, when k′ is 1 and Ar′ is phenyl, L′ is in the paraposition. In another embodiment, k′ is 2. In a subembodiment, when k′ is2 and Ar′ is phenyl, one L′ is in the para position and one L′ is in ameta position. In another embodiment, k′ is 3. In another embodiment, k′is 4. In another embodiment, k′ is 5.

In one embodiment, the compound is selected from the group consistingof:

Enantiomers

In certain embodiments, the compounds are present as enantiomers. In oneembodiment, the compound is provided as an enantiomer or mixture ofenantiomers. In a particular embodiment, the compound is present as aracemic mixture. The enantiomer can be named by the configuration at thechiral center, such as R or S. In certain embodiments, the compound ispresent as a racemic mixture of R- and S-enantiomers. In certainembodiments, the compound is present as a mixture of two enantiomers. Inone embodiment, the mixture has an enantiomeric excess in R. In oneembodiment, the mixture has an enantiomeric excess in S. In certainother embodiments, the compound is in an enantiomeric excess of the R-or S-enantiomer. The enantiomeric excess can be 51% or more, such as 51%or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% ormore, 80% or more, 85% or more, 90% or more, 95% or more, 98% or more,or 99% or more in the single enantiomer. The enantiomeric excess can be51% or more, such as 51% or more, 55% or more, 60% or more, 65% or more,70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% ormore, 98% or more, or 99% or more in the R enantiomer. The enantiomericexcess can be 51% or more, such as 51% or more, 55% or more, 60% ormore, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more,90% or more, 95% or more, 98% or more, or 99% or more in the Senantiomer.

In other embodiments, the compound is substantially in the form of asingle enantiomer. In some embodiments, the compound is presentsubstantially in the form of the R enantiomer. In some embodiments, thecompound is present substantially in the form of the S enantiomer. Thephrase “substantially in the form of a single enantiomer” is intended tomean at least 70% or more in the form of a single enantiomer, forexample 70% or more, 75% or more, 80% or more, 85% or more, 90% or more,95% or more, 98% or more, or 99% or more in either the R or Senantiomer.

The enantiomer can be named by the direction in which it rotates theplane of polarized light. If it rotates the light clockwise as seen bythe viewer towards whom the light is traveling, the isomer can belabeled (+) and if it rotates the light counterclockwise, the isomer canbe labeled (−). In certain embodiments, the compound is present as aracemic mixture of (+) and (−) isomers. In certain embodiments, thecompound is present as a mixture of two isomers. In one embodiment, themixture has an excess in (+). In one embodiment, the mixture has anexcess in (−). In certain other embodiments, the compound is in anexcess of the (+) or (−) isomer. The isomeric excess can be 51% or more,such as 51% or more, 55% or more, 60% or more, 65% or more, 70% or more,75% or more, 80% or more, 85% or more, 90% or more, 95% or more, 98% ormore, or 99% or more in the (+) isomer. The enantiomeric excess can be51% or more, such as 51% or more, 55% or more, 60% or more, 65% or more,70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% ormore, 98% or more, or 99% or more in the (−) isomer.

In other embodiments, the compound is substantially in the form of asingle optical isomer. In some embodiments, the compound is presentsubstantially in the form of the (+) isomer. In other embodiments, thecompound is present substantially in the form of the (−) isomer. Thephrase “substantially in the form of a single optical isomer” isintended to mean at least 70% or more in the form of a single isomer,for example 70% or more, 75% or more, 80% or more, 85% or more, 90% ormore, 95% or more, 98% or more, or 99% or more of either the (+) or (−)isomer.

DEFINITIONS

Whenever a term in the specification is identified as a range (i.e. C₁₋₄alkyl), the range independently refers to each element of the range. Asa non-limiting example, C₁₋₄ alkyl means, independently, C₁, C₂, C₃ orC₄ alkyl. Similarly, when one or more substituents are referred to asbeing “independently selected from” a group, this means that eachsubstituent can be any element of that group, and any combination ofthese groups can be separated from the group. For example, if R¹ and R²can be independently selected from X, Y and Z, this separately includesthe groups R¹ is X and R² is X; R¹ is X and R² is Y; R¹ is X and R² isZ; R¹ is Y and R² is X; R¹ is Y and R² is Y; R¹ is Y and R² is Z; R¹ isZ and R² is X; R¹ is Z and R² is Y; and R¹ is Z and R² is Z.

The term “alkyl” is used herein, unless otherwise specified, refers to asubstituted or unsubstituted, saturated, straight, branched, or cyclic(also identified as cycloalkyl), primary, secondary, or tertiaryhydrocarbon, including but not limited to those of C₁ to C₆.Illustrative examples of alkyl groups are methyl, ethyl, propyl,isopropyl, cyclopropyl, butyl, secbutyl, isobutyl, tertbutyl,cyclobutyl, 1-methylbutyl, 1,1-dimethylpropyl, pentyl, cyclopentyl,isopentyl, neopentyl, cyclopentyl, hexyl, isohexyl, and cyclohexyl.Unless otherwise specified, the alkyl group can be unsubstituted orsubstituted with one or more moieties selected from the group consistingof alkyl, halo, haloalkyl, hydroxyl, carboxyl, acyl, acyloxy, amino,amido, carboxyl derivatives, alkylamino, dialkylamino, arylamino,alkoxy, aryloxy, nitro, cyano, thio, sulfonyl, ester, carboxylic acid,amide, phosphonyl, phosphinyl, thioether, oxime, or any other viablefunctional group that does not inhibit the pharmacological activity ofthis compound, either unprotected, or protected as necessary, as knownto those skilled in the art, for example, as taught in Greene, et al.,Protective Groups in Organic Synthesis, John Wiley and Sons, ThirdEdition, 2002. In certain embodiments, alkyl may be optionallysubstituted by one or more fluoro, chloro, bromo, iodo, hydroxy,heterocyclic, heteroaryl, carboxy, alkoxy, nitro, NH₂, N(alkyl)₂,NH(alkyl), alkoxycarbonyl, —N(H or alkyl)C(O)(H or alkyl), —N(H oralkyl)C(O)N(H or alkyl)₂, —N(H or alkyl)C(O)O(H or alkyl), —OC(O)N(H oralkyl)₂, —S(O)_(n)—(H or alkyl), —C(O)—N(H or alkyl)₂, cyano, alkenyl,cycloalkyl, acyl, hydroxyalkyl, heterocyclic, heteroaryl, aryl,aminoalkyl, oxo, carboxyalkyl, —C(O)—NH₂, —C(O)—N(H)O(H or alkyl),—S(O)₂—NH₂, —S(O)_(n)—N(H or alkyl)₂ and/or —S(O)₂—N(H or alkyl)₂.

The term “cycloalkyl” is used herein, unless otherwise specified, refersto a substituted or unsubstituted, saturated cyclic hydrocarbon,including but not limited to those of C₃ to C₁₂. Illustrative examplesof cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl,cyclopentyl, and cyclohexyl. Unless otherwise specified, the cycloalkylgroup can be unsubstituted or substituted with one or more moietiesselected from the group consisting of alkyl, halo, haloalkyl, hydroxyl,carboxyl, acyl, acyloxy, amino, amido, carboxyl derivatives, alkylamino,dialkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, thio, sulfonyl,ester, carboxylic acid, amide, phosphonyl, phosphinyl, thioether, oxime,or any other viable functional group that does not inhibit thepharmacological activity of this compound, either unprotected, orprotected as necessary, as known to those skilled in the art, forexample, as taught in Greene, et al., Protective Groups in OrganicSynthesis, John Wiley and Sons, Third Edition, 2002. In certainembodiments, the cycloalkyl may be optionally substituted by one or morefluoro, chloro, bromo, iodo, hydroxy, heterocyclic, heteroaryl, carboxy,alkoxy, nitro, NH₂, N(alkyl)₂, NH(alkyl), alkoxycarbonyl, —N(H oralkyl)C(O)(H or alkyl), —N(H or alkyl)C(O)N(H or alkyl)₂, —N(H oralkyl)C(O)O(H or alkyl), —OC(O)N(H or alkyl)₂, —S(O)_(n)—(H or alkyl),—C(O)—N(H or alkyl)₂, cyano, alkenyl, cycloalkyl, acyl, hydroxyalkyl,heterocyclic, heteroaryl, aryl, aminoalkyl, oxo, carboxyalkyl,—C(O)—NH₂, —C(O)—N(H)O(H or alkyl), —S(O)₂—NH₂, —S(O)₂—N(H or alkyl)₂and/or —S(O)₂—N(H or alkyl)₂.

The term “halo” or “halogen,” refers to chloro, bromo, iodo, or fluoro.

The term “heterocyclic” refers to a non-aromatic or aromatic cyclicgroup wherein there is at least one heteroatom, such as oxygen, sulfur,nitrogen, or phosphorus in the ring. The term “heteroaryl” or“heteroaromatic,” refers to an aromatic that includes at least onesulfur, oxygen, nitrogen or phosphorus in the aromatic ring. Nonlimitingexamples of heteroaryl and heterocyclic groups include furyl, furanyl,pyridyl, pyrimidyl, thienyl, isothiazolyl, imidazolyl, tetrazolyl,pyrazinyl, benzofuranyl, benzothiophenyl, quinolyl, isoquinolyl,benzothienyl, isobenzofuryl, pyrazolyl, indolyl, isoindolyl,benzimidazolyl, purinyl, carbazolyl, oxazolyl, thiazolyl, isothiazolyl,1,2,4-thiadiazolyl, isooxazolyl, pyrrolyl, quinazolinyl, cinnolinyl,phthalazinyl, xanthinyl, hypoxanthinyl, thiophene, furan, pyrrole,isopyrrole, pyrazole, imidazole, 1,2,3-triazole, 1,2,4-triazole,oxazole, isoxazole, thiazole, isothiazole, pyrimidine or pyridazine,pteridinyl, aziridines, thiazole, isothiazole, oxadiazole, thiazine,pyridine, pyrazine, piperazine, piperidine, pyrrolidine, oxaziranes,phenazine, phenothiazine, morpholinyl, pyrazolyl, pyridazinyl,pyrazinyl, quinoxalinyl, xanthinyl, hypoxanthinyl, pteridinyl,5-azacytidinyl, 5-azauracilyl, triazolopyridinyl, imidazolopyridinyl,pyrrolopyrimidinyl, pyrazolopyrimidinyl, adenine, N⁶-alkylpurines,N⁶-benzylpurine, N⁶-halopurine, N⁶-vinypurine, N⁶-acetylenic purine,N⁶-acyl purine, N⁶-hydroxyalkyl purine, N⁶-thioalkyl purine, thymine,cytosine, 6-azapyrimidine, 2-mercaptopyrmidine, uracil,N⁵-alkylpyrimidines, N⁵-benzylpyrimidines, N⁵-halopyrimidines,N⁵-vinylpyrimidine, N⁵-acetylenic pyrimidine, N⁵-acyl pyrimidine,N⁵-hydroxyalkyl purine, and N⁶-thioalkyl purine, and isoxazolyl. Theheteroaromatic or heterocyclic group can be optionally substituted withone or more substituent selected from halogen, haloalkyl, alkyl, alkoxy,hydroxy, carboxyl derivatives, amido, amino, alkylamino, dialkylamino.The heteroaromatic can be partially or totally hydrogenated as desired.Nonlimiting examples include dihydropyridine andtetrahydrobenzimidazole. In some embodiment, the heteroaryl may beoptionally substituted by one or more fluoro, chloro, bromo, iodo,hydroxy, heterocyclic, heteroaryl, carboxy, alkoxy, nitro, NH₂,N(alkyl)₂, NH(alkyl), alkoxycarbonyl, —N(H or alkyl)C(O)(H or alkyl),—N(H or alkyl)C(O)N(H or alkyl)₂, —N(H or alkyl)C(O)O(H or alkyl),—OC(O)N(H or alkyl)₂, —S(O)_(n)—(H or alkyl), —C(O)—N(H or alkyl)₂,cyano, alkenyl, cycloalkyl, acyl, hydroxyalkyl, heterocyclic,heteroaryl, aryl, aminoalkyl, oxo, carboxyalkyl, —C(O)—NH₂,—C(O)—N(H)O(H or alkyl), —S(O)₂—NH₂, —S(O)_(n)—N(H or alkyl)₂ and/or—S(O)₂—N(H or alkyl)₂. Functional oxygen and nitrogen groups on theheteroaryl group can be protected as necessary or desired. Suitableprotecting groups are well known to those skilled in the art, andinclude trimethylsilyl, dimethylhexylsilyl, t-butyldimethylsilyl, andt-butyldiphenylsilyl, trityl or substituted trityl, alkyl groups, acylgroups such as acetyl and propionyl, methanesulfonyl, andp-tolylsulfonyl.

The term “aryl,” unless otherwise specified, refers to a carbon basedaromatic ring, including phenyl, biphenyl, or naphthyl. The aryl groupcan be optionally substituted with one or more moieties selected fromthe group consisting of hydroxyl, acyl, amino, halo, alkylamino, alkoxy,aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid,phosphate, or phosphonate, either unprotected, or protected asnecessary, as known to those skilled in the art, for example, as taughtin Greene, et al. Protective Groups in Organic Synthesis, John Wiley andSons, Third Edition, 2002. In certain embodiments, the aryl group isoptionally substituted by one or more fluoro, chloro, bromo, iodo,hydroxy, heterocyclic, heteroaryl, carboxy, alkoxy, nitro, NH₂,N(alkyl)₂, NH(alkyl), alkoxycarbonyl, —N(H or alkyl)C(O)(H or alkyl),—N(H or alkyl)C(O)N(H or alkyl)₂, —N(H or alkyl)C(O)O(H or alkyl),—OC(O)N(H or alkyl)₂, —S(O)_(n)—(H or alkyl), —C(O)—N(H or alkyl)₂,cyano, alkenyl, cycloalkyl, acyl, hydroxyalkyl, heterocyclic,heteroaryl, aryl, aminoalkyl, oxo, carboxyalkyl, —C(O)—NH₂,—C(O)—N(H)O(H or alkyl), —S(O)₂—NH₂, —S(O)_(n)—N(H or alkyl)₂ and/or—S(O)₂—N(H or alkyl)₂.

The term “aralkyl,” unless otherwise specified, refers to an aryl groupas defined above linked to the molecule through an alkyl group asdefined above.

The term “alkaryl,” unless otherwise specified, refers to an alkyl groupas defend above linked to the molecule through an aryl group as definedabove. Other groups, such as acyloxyalkyl, alkoxyalkyl, alkoxycarbonyl,alkoxycarbonylalkyl, alkylaminoalkyl, alkylthioalkyl, amidoalkyl,aminoalkyl, carboxyalkyl, dialkylaminoalkyl, haloalkyl, heteroaralkyl,heterocyclicalkyl, hydroxyalkyl, sulfonamidoalkyl, sulfonylalkyl andthioalkyl are named in a similar manner.

The term “alkoxy,” unless otherwise specified, refers to a moiety of thestructure —O-alkyl, wherein alkyl is as defined above.

The term “acyl,” refers to a group of the formula C(O)R′ or “alkyl-oxy”,wherein R′ is an alkyl, aryl, alkaryl or aralkyl group, or substitutedalkyl, aryl, aralkyl or alkaryl.

The term “alkenyl” The term “alkenyl” means a monovalent, unbranched orbranched hydrocarbon chain having one or more double bonds therein. Thedouble bond of an alkenyl group can be unconjugated or conjugated toanother unsaturated group. Suitable alkenyl groups include, but are notlimited to (C₂-C₈)alkenyl groups, such as vinyl, allyl, butenyl,pentenyl, hexenyl, butadienyl, pentadienyl, hexadienyl, 2-ethylhexenyl,2-propyl-2-butenyl, 4-(2-methyl-3-butene)-pentenyl. An alkenyl group canbe unsubstituted or substituted with one or two suitable substituents.

The term “carbonyl” refers to a functional group composed of a carbonatom double-bonded to an oxygen atom: —C═O, Similarly, C(O) or C(═O)refers to a carbonyl group.

The term “amino” refers to —NH₂, —NH(alkyl) or —N(alkyl)₂.

The term “thio” indicates the presence of a sulfur group. The prefixthio- denotes that there is at least one extra sulfur atom added to thechemical. The prefix ‘thio-’ can also be placed before the name of acompound to mean that an oxygen atom in the compound has been replacedby a sulfur atom. Although typically the term “thiol” is used toindicate the presence of —SH, in instances in which the sulfur atomwould be have improper valance a radical if the hydrogen is improperlydesignated, the terms ‘thio’ and ‘thiol’ are used interchangeably,unless otherwise indicated.

The term “amido” indicates a group (H or alkyl)-C(O)—NH—.

The term “carboxy” designates the terminal group —C(O)OH.

The term “sulfonyl” indicates an organic radical of the general formula(H or alkyl)-S(═O)₂—(H or alkyl′), where there are two double bondsbetween the sulfur and oxygen.

The term “pharmaceutically acceptable salt” refers to salts or complexesthat retain the desired biological activity of the compounds of thepresent invention and exhibit minimal undesired toxicological effects.Nonlimiting examples of such salts are (a) acid addition salts formedwith inorganic acids (for example, hydrochloric acid, hydrobromic acid,sulfuric acid, phosphoric acid, nitric acid, and the like), and saltsformed with organic acids such as acetic acid, oxalic acid, tartaricacid, succinic acid, malic acid, ascorbic acid, benzoic acid, tannicacid, pamoic acid, alginic acid, polyglutamic acid, naphthalenesulfonicacid, naphthalenedisulfonic acid, and polygalcturonic acid; (b) baseaddition salts formed with metal cations such as zinc, calcium, bismuth,barium, magnesium, aluminum, copper, cobalt, nickel, cadmium, sodium,potassium, and the like, or with a cation formed from ammonia,N,N-dibenzylethylenediamine, D-glucosamine, tetraethylammonium, orethylenediamine; or (c) combinations of (a) and (b); e.g., a zinctannate salt or the like. Also included in this definition arepharmaceutically acceptable quaternary salts known by those skilled inthe art, which specifically include the quaternary ammonium salt of theformula —NR⁺A⁻, wherein R is H or alkyl and A is a counterion, includingchloride, bromide, iodide, —O-alkyl, toluenesulfonate, methylsulfonate,sulfonate, phosphate, or carboxylate (such as benzoate, succinate,acetate, glycolate, maleate, malate, citrate, tartrate, ascorbate,benzoate, cinnamoate, mandeloate, benzyloate, and diphenylacetate).

The term “protected” as used herein and unless otherwise defined refersto a group that is added to an oxygen, nitrogen, or phosphorus atom toprevent its further reaction or for other purposes. A wide variety ofoxygen and nitrogen protecting groups are known to those skilled in theart of organic synthesis.

It should be understood that the various possible stereoisomers of thegroups mentioned above and herein are within the meaning of theindividual terms and examples, unless otherwise specified. As anillustrative example, “1-methyl-butyl” exists in both (R) and the (S)form, thus, both (R)-1-methyl-butyl and (S)-1-methyl-butyl is covered bythe term “1-methyl-butyl”, unless otherwise specified.

Methods of Use

The compounds described herein can generally be used to treatneuropathic pain, stroke, traumatic brain injury, epilepsy, and otherneurologic events or neurodegeneration resulting from NMDA receptoractivation. Methods are provided for the treatment neuropathic pain,stroke, traumatic brain injury, epilepsy, and other neurologic events orneurodegeneration resulting from NMDA receptor activation comprisingadministering to a host in need thereof an effective amount of acompound of Formula I, II, III, IV or V, or a pharmaceutical compositionthereof. In specific embodiments, the compound is of Formula I or V, ora salt or ester thereof.

In one embodiment, a method of treatment for neuropathic pain, stroke,traumatic brain injury, epilepsy, and other neurologic events orneurodegeneration resulting from NMDA receptor activation comprisingadministering a neuroprotective agent of Formula I is provided.Compositions and methods comprising the compounds described herein areuseful for treating neuropathic pain, stroke, traumatic brain injury,epilepsy, and other neurologic events or neurodegeneration resultingfrom NMDA receptor activation. In one embodiment, methods are useful inthe treatment of neuropathic pain. In another embodiment, the methodsare useful in preventing neurodegeneration in patients with Parkinson's,Alzheimer's, Huntington's chorea, ALS, and other neurodegenerativeconditions known to the art to be responsive to treatment using NMDAreceptor blockers.

The compounds of the invention can generally be administered to a hostat risk of, or suffering from, neuropathic pain, stroke, traumatic braininjury, epilepsy, and other neurologic events or neurodegenerationresulting from NMDA receptor activation. In one embodiment, thecompounds are administered for the treatment or prophylaxis of anneuropathic pain, stroke, traumatic brain injury, epilepsy, and otherneurologic events or neurodegeneration resulting from NMDA receptoractivation.

In additional aspects of the present invention, methods are provided totreat patients by administering a compound selected according to themethods or processes described herein. Any disease, condition ordisorder which induces a region with a reduced pH (below pH 7.6) can betreated according to the methods described herein.

Certain NMDA receptor antagonists described herein have enhancedactivity in tissue having lower-than-normal pH. The tissue can be braintissue. In certain embodiments, the reduced pH is due to pathologicalconditions such as hypoxia resulting from stroke, traumatic braininjury, global ischemia, such as global ischemia that may occur duringcardiac surgery, hypoxia, including hypoxia that may occur followingcessation of breathing, pre-eclampsia, spinal cord trauma, epilepsy,status epilepticus, neuropathic pain, inflammatory pain, chronic pain,vascular dementia and glioma tumors. Because tumors produce an acidicenvironment, drugs activated by low pH can be useful in slowing tumorgrowth because they have enhanced activity only at the site of thetumor. In some embodiments, the compounds are useful in the treatment oftumor growth. In certain embodiments, the compounds reduce tumor mass.In one embodiment, the compounds are useful in the treatment orprophylaxis of a neurologic event involving acidification of brain orspinal cord tissue. In another embodiment, the NMDA receptor antagonistsof this invention are useful both in the treatment of stroke and headtrauma, and for use as prophylactic agents for at risk patients. Theacid generated by ischemic tissue during stroke is harnessed as a switchto activate the neuroprotective agents described herein. In this wayside effects are minimized in unaffected tissue since drug at thesesites are less active. These compounds may be used to reduce the amountof neuronal death associated with stroke and head trauma. They may begiven chronically to individuals with epilepsy or who are at risk forstroke or head trauma, preoperatively in high risk heart/brain surgery,etc., in order to lengthen the window of opportunity for subsequenttherapy.

In one embodiment, methods are provided to attenuate the progression ofan ischemic or excitotoxic cascade associated with a drop in pH byadministering a compound described herein. In addition, methods areprovided to decrease infarct volume associated with a drop in pH byadministering a compound selected according to the processes or methodsdescribed herein. Further, a method is provided to decrease cell deathassociated with a drop in pH by administering a compound selectedaccording to the processes or methods described herein. Still further,methods are provided to decrease behavioral deficits associated with anischemic event associated with a drop in pH by administering a compoundselected according to the processes or methods described herein.

In additional aspects of the present invention, methods are provided totreat patients in need thereof by administering a compound orcomposition described herein. Any disease, condition or disorder whichinduces a low pH can be treated according to the methods describedherein.

In one embodiment, methods are provided to treat patients with ischemicinjury or hypoxia, or prevent or treat the neuronal toxicity associatedwith ischemic injury or hypoxia, by administering a compound orcomposition described herein. In one particular embodiment, the ischemicinjury is stroke. In another particular embodiment, the ischemic injuryis vasospasm after subarachnoid hemorrhage. In other embodiments, theischemic injury is selected from, but not limited to, one of thefollowing: traumatic brain injury, cognitive deficit after bypasssurgery, cognitive deficit after carotid angioplasty; and/or neonatalischemia following hypothermic circulatory arrest.

In another embodiment, methods are provided to treat patients withneuropathic pain or related disorders by administering a compound orcomposition described herein. In certain embodiments, the neuropathicpain or related disorder can be selected from the group including, butnot limited to: peripheral diabetic neuropathy, postherpetic neuralgia,complex regional pain syndromes, peripheral neuropathies,chemotherapy-induced neuropathic pain, cancer neuropathic pain,neuropathic low back pain, HIV neuropathic pain, trigeminal neuralgia,and/or central post-stroke pain.

In another embodiment, methods are provided to treat patients with braintumors by administering a compound selected according to the methods orprocesses described herein. In a further embodiment, methods areprovided to treat patients with neurodegenerative diseases byadministering a compound selected according to the methods or processesdescribed herein. In one embodiment, the neurodegenerative disease canbe Parkinson's disease. In another embodiment, the neurodegenerativedisease can be Alzheimer's, Huntington's and/or Amyotrophic LateralSclerosis.

Further, compounds selected according to the methods or processesdescribed herein can be used prophylactically to prevent or protectagainst such diseases or neurological conditions, such as thosedescribed herein. In one embodiment, patients with a predisposition foran ischemic event, such as a genetic predisposition, can be treatedprophylactically with the methods and compounds described herein. Inanother embodiment, patients that exhibit vasospasms can be treatedprophylactically with the methods and compounds described herein. In afurther embodiment, patients that have undergone cardiac bypass surgerycan be treated prophylactically with the methods and compounds describedherein.

In one embodiment, methods are provided to treat patients with ischemicinjury or hypoxia, or prevent or treat the neuronal toxicity associatedwith ischemic injury or hypoxia, by administering a compound selectedaccording to the methods or processes described herein. In oneparticular embodiment, the ischemic injury can be stroke. In otherembodiments, the ischemic injury can be selected from, but not limitedto, one of the following: traumatic brain injury, cognitive deficitafter bypass surgery, cognitive deficit after carotid angioplasty;and/or neonatal ischemia following hypothermic circulatory arrest.

In another particular embodiment, the ischemic injury can be vasospasmafter subarachnoid hemorrhage. A subarachnoid hemorrhage refers to anabnormal condition in which blood collects beneath the arachnoid mater,a membrane that covers the brain. This area, called the subarachnoidspace, normally contains cerebrospinal fluid. The accumulation of bloodin the subarachnoid space and the vasospasm of the vessels which resultsfrom it can lead to stroke, seizures, and other complications. Themethods and compounds described herein can be used to treat patientsexperiencing a subarachnoid hemorrhage. In one embodiment, the methodsand compounds described herein can be used to limit the toxic effects ofthe subarachnoid hemorrhage, including, for example, stroke and/orischemia that can result from the subarachnoid hemorrhage. In aparticular embodiment, the methods and compounds described herein can beused to treat patients with traumatic subarachnoid hemorrhage. On oneembodiment, the traumatic subarachnoid hemorrhage can be due to a headinjury. In another embodiment, the patients can have a spontaneoussubarachnoid hemorrhage.

In another embodiment, methods are provided to treat patients withneuropathic pain or related disorders by administering a compoundselected according to the methods or processes described herein. Incertain embodiments, the neuropathic pain or related disorder can beselected from the group including, but not limited to: peripheraldiabetic neuropathy, postherpetic neuralgia, complex regional painsyndromes, peripheral neuropathies, chemotherapy-induced neuropathicpain, cancer neuropathic pain, neuropathic low back pain, HIVneuropathic pain, trigeminal neuralgia, and/or central post-stroke pain.

Neuropathic pain can be associated with signals generated ectopicallyand often in the absence of ongoing noxious events by pathologicprocesses in the peripheral or central nervous system. This dysfunctioncan be associated with common symptoms such as allodynia, hyperalgesia,intermittent abnormal sensations, and spontaneous, burning, shooting,stabbing, paroxysmal or electrical-sensations, paresthesias, hyperpathiaand/or dysesthesias, which can also be treated by the compounds andmethods described herein.

Further, the compounds and methods described herein can be used to treatneuropathic pain resulting from peripheral or central nervous systempathologic events, including, but not limited to trauma, ischemia;infections or from ongoing metabolic or toxic diseases, infections orendocrinologic disorders, including, but not limited to, diabetesmellitus, diabetic neurophathy, amyloidosis, amyloid polyneuropathy(primary and familial), neuropathies with monoclonal proteins,vasculitic neuropathy, HIV infection, herpes zoster—shingles and/orpostherpetic neuralgia; neuropathy associated with Guillain-Barresyndrome; neuropathy associated with Fabry's disease; entrapment due toanatomic abnormalities; trigeminal and other CNS neuralgias;malignancies; inflammatory conditions or autoimmune disorders,including, but not limited to, demyelinating inflammatory disorders,rheumatoid arthritis, systemic lupus erythematosus, Sjogren's syndrome;and cryptogenic causes, including, but not limited to idiopathic distalsmall-fiber neuropathy. Other causes of neuropathic pain that can betreated according to the methods and compositions described hereininclude, but are not limited to, exposure to toxins or drugs (such asarsenic, thallium, alcohol, vincristine, cisplatinum anddideoxynucleosides), dietary or absorption abnormalities,immuno-globulinemias, hereditary abnormalities and amputations(including mastectomy). Neuropathic pain can also result fromcompression of nerve fibers, such as radiculopathies and carpal tunnelsyndrome.

In another embodiment, methods are provided to treat patients with braintumors by administering a compound selected according to the methods orprocesses described herein. In a further embodiment, methods areprovided to treat patients with neurodegenerative diseases byadministering a compound selected according to the methods or processesdescribed herein. In one embodiment, the neurodegenerative disease canbe Parkinson's disease. In another embodiment, the neurodegenerativedisease can be Alzheimer's, Huntington's and/or Amyotrophic LateralSclerosis.

In another embodiment, the methods provided herein can be usedprophylactically to prevent or protect against such diseases orneurological conditions, such as those described herein. In oneembodiment, patients with a predisposition for an ischemic event, suchas a genetic predisposition, can be treated prophylactically with themethods and compounds described herein. In another embodiment, patientsthat exhibit vasospasms can be treated prophylactically with the methodsand compounds described herein. In further embodiment, patients thathave undergone cardiac bypass surgery can be treated prophylacticallywith the methods and compounds described herein.

In addition, methods are provided to treat the following diseases orneurological conditions, including, but not limited to: chronic nerveinjury, chronic pain syndromes, such as, but not limited to diabeticneuropathy, ischemia, ischemia following transient or permanent vesselocclusion, seizures, spreading depression, restless leg syndrome,hypocapnia, hypercapnia, diabetic ketoacidosis, fetal asphyxia, spinalcord injury, traumatic brain injury, status epilepticus, epilepsy,hypoxia, perinatal hypoxia, concussion, migraine, hypocapnia,hyperventilation, lactic acidosis, fetal asphyxia during parturition,brain gliomas, and/or retinopathies by administering a compound selectedaccording to the methods or processes described herein.

Further provided are methods to attenuate the progression of anischemic, hypoxic or excitotoxic cascade associated with a drop in pH byadministering an effective amount of a compound that exhibits theproperties described herein. In addition, methods are provided todecrease infarct volume associated with a drop in pH by administering acompound that exhibits the properties described herein. Further, amethod is provided to decrease cell death associated with a drop in pHby administering a compound that exhibits the properties describedherein. Still further, methods are provided to decrease behavioraldeficits associated with an ischemic event associated with a drop in pHby administering a compound that exhibits the properties describedherein.

In one embodiment, the use of the compounds of the invention reducessymptoms of neuropathic pain, stroke, traumatic brain injury, epilepsy,and other neurologic events or neurodegeneration resulting from NMDAreceptor activation.

Side Effects

In an additional aspect of the methods and processes described herein,the compound does not exhibit substantial toxic an/or psychotic sideeffects. Toxic side effects include, but are not limited to, agitation,hallucination, confusion, stupor, paranoia, delirium,psychotomimetic-like symptoms, rotarod impairment, amphetamine-likestereotyped behaviors, stereotypy, psychosis memory impairment, motorimpairment, anxiolytic-like effects, increased blood pressure, decreasedblood pressure, increased pulse, decreased pulse, hematologicalabnormalities, electrocardiogram (ECG) abnormalities, cardiac toxicity,heart palpitations, motor stimulation, psychomotor performance, moodchanges, short-term memory deficits, long-term memory deficits, arousal,sedation, extrapyramidal side-effects, ventricular tachycardia.Lengthening of cardiac repolarisation, ataxia, cognitive deficits and/orschizophrenia-like symptoms.

In one embodiment, the compounds are selective NMDA receptor blockers.General blocking of NMDA receptors throughout the brain causes adverseeffects such as ataxia, memory deficits, hallucinations and otherneurological problems. The compounds provided herein can selectivelyblock NR2B-containing NMDA receptors, have varying activity againstreceptors containing NR2A or NR2D, and may also be selective for othermembers of the NMDA receptor family (NR2C, NR3A and NR3B). IIn oneembodiment, the compounds are NMDA receptors antagonists selective forNR2B, NR2A, NR2C, NR2D, NR3A, and/or NR3B and do not interact with otherreceptors or ion channels at therapeutic concentrations. In oneembodiment, the compound is a selective NR1/NR2A NMDA receptor and/or aNR1/NR2B NMDA receptor antagonist. In one particular embodiment, thecompounds can bind to the NR2B subunit of the NMDA receptor. In anotherparticular embodiment, the compounds are selective for the NR2B subunitof the NMDA receptor. In one embodiment, the compound is not an NMDAreceptor glutamate site antagonist. In another embodiment, the compoundis not an NMDA receptor glycine site antagonist.

The compounds selected or identified according to the processes andmethods described herein generally avoid substantial side effectsassociated with other classes of NMDA receptor antagonists. In oneembodiments, such compounds do not substantially exhibit the sideeffects associated with NMDA antagonists of the glutamate site, such asselfotel, D-CPPene (SDZ EAA 494) and AR-R15896AR (ARL 15896AR),including, agitation, hallucination, confusion and stupor (Davis et al.(2000) Stroke 31(2):347-354; Diener et al. (2002), J Neurol249(5):561-568); paranoia and delirium (Grotta et al. (1995), J InternMed 237:89-94); psychotomimetic-like symptoms (Loscher et al. (1998),Neurosci Lett 240(1):33-36); poor therapeutic ratio (Dawson et al.(2001), Brain Res 892(2):344-350); amphetamine-like stereotypedbehaviors (Potschka et al. (1999), Eur J Pharmacol 374(2):175-187). Inanother embodiment, such compounds do not exhibit the side effectsassociated with NMDA antagonists of the glycine site, such as HA-966,L-701,324, d-cycloserine, CGP-40116, and ACEA 1021, includingsignificant memory impairment and motor impairment (Wlaz, P (1998),Brain Res Bull 46(6):535-540). In a still further embodiment, suchcompounds do not exhibit the side effects of NMDA high affinity receptorchannel blockers, such as MK-801 and ketamine, including, psychosis-likeeffects (Hoffman, D C (1992), J Neural Transm Gen Sect 89:1-10);cognitive deficits (decrements in free recall, recognition memory, andattention; Malhotra et al (1996), Neuropsychopharmacology 14:301-307);schizophrenia-like symptoms (Krystal et al (1994), Arch Gen Psychiatry51:199-214; Lahti et al. (2001), Neuropsychopharmacology 25:455-467),and hyperactivity and increased stereotpy (Ford et al (1989) Physiologyand behavior 46: 755-758.

In a further additional or alternative embodiment, the compound has atherapeutic index equal to or greater than at least 2:1, at least 3:1,at least 4:1, at least 5:1, at least 6:1, at least 7:1, at least 8:1, atleast 9:1, at least 10:1, at least 15:1, at least 20:1, at least 25:1,at least 30:1, at least 40:1, at least 50:1, at least 75:1, at least100:1 or at least 1000:1. The therapeutic index can be defined as theratio of the dose required to produce toxic or lethal effects to doserequired to produce therapeutic responses. It can be the ratio betweenthe median toxic dose (the dosage at which 50% of the group exhibits theadverse effect of the drug) and the median effective dose (the dosage atwhich 50% of the population respond to the drug in a specific manner).The higher the therapeutic index, the more safe the drug is consideredto be. It simply indicates that it would take a higher dose to invoke atoxic response that it does to cause a beneficial effect.

The side effect profile of compounds can be determined by any methodknown to those skilled in the art. In one embodiment, motor impairmentcan be measured by, for example, measuring locomotor activity and/orrotorod performance. Rotorod experiments involve measuring the durationthat an animal can remain on an accelerating rod. In another embodiment,memory impairment can be assessed, for example, by using a passiveavoidance paradigm; Sternberg memory scanning and paired words forshort-term memory, or delayed free recall of pictures for long-termmemory. In a further embodiment, anxiolytic-like effects can bemeasured, for example, in the elevated plus maze task. In otherembodiments, cardiac function can be monitored, blood pressure and/orbody temperature measured and/or electrocardiograms conducted to testfor side effects. In other embodiments, psychomotor functions andarousal can be measured, for example by analyzing critical flickerfusion threshold, choice reaction time, and/or body sway. In otherembodiments, mood can be assessed using, for example, self-ratings. Infurther embodiments, schizophrenic symptoms can be evaluated, forexample, using the PANSS, BPRS, and CGI, side-effects were assessed bythe HAS and the S/A scale.

In one embodiment, the compound does not exhibit substantial toxic sideeffects, such as, for example, motor impairment or cognitive impairment.In a particular embodiment, the compound has a therapeutic index equalto or greater than at least 2. In another embodiment, the compound is atleast 10 times more selective for binding to an NMDA receptor than anyother glutamate receptor. In certain embodiments, the compound activateshERG receptors at an IC₅₀ at least 10 times the IC₅₀ of inhibition of anNMDA receptor at either pH 6.9 or 7.6 or both. In certain embodiments,the compound activates adrenergic receptors, in particular a adrenergicsuch as α1 adrenergic receptors at an IC₅₀ at least 10 times the IC₅₀ ofinhibition of an NMDA receptor at either pH 6.9 or 7.6 or both. Inspecific embodiments the ratio of IC₅₀'s between either hERG activationor adrenergic receptor activation and NMDA receptor antagonism isgreater than 50, or greater than 100, or greater than 500.

Pharmaceutical Compositions

Mammals, and specifically humans, suffering from neuropathic pain,stroke, traumatic brain injury, epilepsy, and other neurologic events orneurodegeneration resulting from NMDA receptor activation, or any of theabove-described conditions, and in particular suffering from neuropathicpain, can be treated by either targeted or systemic administration, viaoral, inhalation, topical, trans- or sub-mucosal, subcutaneous,parenteral, intramuscular, intravenous or transdermal administration ofa composition comprising an effective amount of the compounds describedherein or a pharmaceutically acceptable salt, ester or prodrug thereof,optionally in a pharmaceutically acceptable carrier.

The compounds or composition is typically administered by oraladministration. Alternatively, compounds can be administered byinhalation. In another embodiment, the compound is administeredtransdermally (for example via a slow release patch), or topically. Inyet another embodiment, the compound is administered subcutaneously,intravenously, intraperitoneally, intramuscularly, parenterally, orsubmucosally. In any of these embodiments, the compound is administeredin an effective dosage range to treat the target condition.

In one embodiment, compounds of the present invention are administeredorally. Oral compositions will generally include an inert diluent or anedible carrier. They may be enclosed in gelatin capsules or compressedinto tablets. For the purpose of oral therapeutic administration, theactive compound can be incorporated with excipients and used in the formof tablets, troches, or capsules. Pharmaceutically compatible bindingagents, and/or adjuvant materials can be included as part of thecomposition.

When the compound is administered orally in the form of a dosage unitsuch as a tablets, pills, capsules, troches and the like, these cancontain any of the following ingredients, or compounds of a similarnature: a binder (such as microcrystalline cellulose, gum tragacanth orgelatin); an excipient (such as starch or lactose), a disintegratingagent (such as alginic acid, Primogel, or corn starch); a lubricant(such as magnesium stearate or Sterotes); a glidant (such as colloidalsilicon dioxide); a sweetening agent (such as sucrose or saccharin);and/or a flavoring agent (such as peppermint, methyl salicylate, ororange flavoring). When the dosage unit form is a capsule, it cancontain, in addition to material of the above type, a liquid carrier(such as a fatty oil). In addition, dosage unit forms can containvarious other materials which modify the physical form of the dosageunit, for example, coatings of sugar, shellac, or other enteric agents.

The compound or its salts can also be administered orally as a componentof an elixir, suspension, syrup, wafer, chewing gum or the like. A syrupmay contain, in addition to the active compounds, a sweetening agent(such as sucrose, saccharine, etc.) and preservatives, dyes andcolorings and flavors.

The compounds of the invention may be also administered in specific,measured amounts in the form of an aqueous suspension by use of a pumpspray bottle. The aqueous suspension compositions of the presentinvention may be prepared by admixing the compounds with water and otherpharmaceutically acceptable excipients. The aqueous suspensioncompositions according to the present invention may contain, inter alia,water, auxiliaries and/or one or more of the excipients, such as:suspending agents, e.g., microcrystalline cellulose, sodiumcarboxymethylcellulose, hydroxpropyl-methyl cellulose; humectants, e.g.glycerin and propylene glycol; acids, bases or buffer substances foradjusting the pH, e.g., citric acid, sodium citrate, phosphoric acid,sodium phosphate as well as mixtures of citrate and phosphate buffers;surfactants, e.g. Polysorbate 80; and antimicrobial preservatives, e.g.,benzalkonium chloride, phenylethyl alcohol and potassium sorbate.

In a separate embodiment, the compounds of the invention are in the formof an inhaled dosage. In this embodiment, the compounds may be in theform of an aerosol suspension, a dry powder or liquid particle form. Thecompounds may be prepared for delivery as a nasal spray or in aninhaler, such as a metered dose inhaler. Pressurized metered-doseinhalers (“MDI”) generally deliver aerosolized particles suspended inchlorofluorocarbon propellants such as CFC-11, CFC-12, or thenon-chlorofluorocarbons or alternate propellants such as thefluorocarbons, HFC-134A or HFC-227 with or without surfactants andsuitable bridging agents. Dry-powder inhalers can also be used, eitherbreath activated or delivered by air or gas pressure such as thedry-powder inhaler disclosed in the Schering Corporation InternationalPatent Application No. PCT/US92/05225, published 7 Jan. 1993 as well asthe Turbuhaler™ (available from Astra Pharmaceutical Products, Inc.) orthe Rotahaler™ (available from Allen & Hanburys) which may be used todeliver the aerosolized particles as a finely milled powder in largeaggregates either alone or in combination with some pharmaceuticallyacceptable carrier e.g. lactose; and nebulizers.

Solutions or suspensions used for parenteral, intradermal, subcutaneous,or topical application can include at least some of the followingcomponents: a sterile diluent (such as water for injection, salinesolution, fixed oils, polyethylene glycols, glycerine, propylene glycolor other synthetic solvents); antibacterial agents (such as benzylalcohol or methyl parabens); antioxidants (such as ascorbic acid orsodium bisulfate); chelating agents (such as ethylenediaminetetraaceticacid); buffers (such as acetates, citrates or phosphates); and/or agentsfor the adjustment of tonicity (such as sodium chloride or dextrose).The pH of the solution or suspension can be adjusted with acids orbases, such as hydrochloric acid or sodium hydroxide.

A parenteral preparation can be enclosed in ampoules, disposablesyringes or multiple dose vials made of glass or plastic.

Suitable vehicles or carriers for topical application can be prepared byconventional techniques, such as lotions, suspensions, ointments,creams, gels, tinctures, sprays, powders, pastes, slow-releasetransdermal patches, suppositories for application to rectal, vaginal,nasal or oral mucosa. In addition to the other materials listed abovefor systemic administration, thickening agents, emollients, andstabilizers can be used to prepare topical compositions. Examples ofthickening agents include petrolatum, beeswax, xanthan gum, orpolyethylene, humectants such as sorbitol, emollients such as mineraloil, lanolin and its derivatives, or squalene.

If administered intravenously, carriers can be physiological saline,bacteriostatic water, Cremophor EL™ (BASF, Parsippany, N.J.) orphosphate buffered saline (PBS).

In one embodiment, the active compounds are prepared with carriers thatwill protect the compound against rapid elimination from the body, suchas a controlled release formulation, including implants andmicroencapsulated delivery systems. Biodegradable, biocompatiblepolymers can be used, such as ethylene vinyl acetate, polyanhydrides,polyglycolic acid, collagen, polyorthoesters, and polylactic acid.Methods for preparation of such formulations will be apparent to thoseskilled in the art. The materials can also be obtained commercially fromAlza Corporation and Nova Pharmaceuticals, Inc. Liposomal suspensions(including liposomes targeted to infected cells with monoclonalantibodies to viral antigens) are also preferred as pharmaceuticallyacceptable carriers. These may be prepared according to methods known tothose skilled in the art, for example, as described in U.S. Pat. No.4,522,811 (which is incorporated herein by reference in its entirety).For example, liposome formulations may be prepared by dissolvingappropriate lipid(s) (such as stearoyl phosphatidyl ethanolamine,stearoyl phosphatidyl choline, arachadoyl phosphatidyl choline, andcholesterol) in an inorganic solvent that is then evaporated, leavingbehind a thin film of dried lipid on the surface of the container. Anaqueous solution of the compound is then introduced into the container.The container is then swirled by hand to free lipid material from thesides of the container and to disperse lipid aggregates, thereby formingthe liposomal suspension.

Dosing

The compound is administered for a sufficient time period to alleviatethe undesired symptoms and the clinical signs associated with thecondition being treated. In one embodiment, the compounds areadministered less than three times daily. In one embodiment, thecompounds are administered in one or two doses daily. In one embodiment,the compounds are administered once daily. In some embodiments, thecompounds are administered in a single oral dosage once a day.

The active compound is included in the pharmaceutically acceptablecarrier or diluent in an amount sufficient to deliver to a patient atherapeutic amount of compound in vivo in the absence of serious toxiceffects. An effective dose can be readily determined by the use ofconventional techniques and by observing results obtained underanalogous circumstances. In determining the effective dose, a number offactors are considered including, but not limited to: the species ofpatient; its size, age, and general health; the specific diseaseinvolved; the degree of involvement or the severity of the disease; theresponse of the individual patient; the particular compoundadministered; the mode of administration; the bioavailabilitycharacteristics of the preparation administered; the dose regimenselected; and the use of concomitant medication.

Typical systemic dosages for the herein described conditions are thoseranging from 0.01 mg/kg to 1500 mg/kg of body weight per day as a singledaily dose or divided daily doses. Preferred dosages for the describedconditions range from 0.5-1500 mg per day. A more particularly preferreddosage for the desired conditions ranges from 5-750 mg per day. Typicaldosages can also range from 0.01 to 1500, 0.02 to 1000, 0.2 to 500, 0.02to 200, 0.05 to 100, 0.05 to 50, 0.075 to 50, 0.1 to 50, 0.5 to 50, 1 to50, 2 to 50, 5 to 50, 10 to 50, 25 to 50, 25 to 75, 25 to 100, 100 to150, or 150 or more mg/kg/day, as a single daily dose or divided dailydoses. In one embodiment, the daily dose is between 10 and 500 mg/day.In another embodiment, the dose is between about 10 and 400 mg/day, orbetween about 10 and 300 mg/day, or between about 20 and 300 mg/day, orbetween about 30 and 300 mg/day, or between about 40 and 300 mg/day, orbetween about 50 and 300 mg/day, or between about 60 and 300 mg/day, orbetween about 70 and 300 mg/day, or between about 80 and 300 mg/day, orbetween about 90 and 300 mg/day, or between about 100 and 300 mg/day, orabout 200 mg/day. In one embodiment, the compounds are given in doses ofbetween about 1 to about 5, about 5 to about 10, about 10 to about 25 orabout 25 to about 50 mg/kg. Typical dosages for topical application arethose ranging from 0.001 to 100% by weight of the active compound.

The concentration of active compound in the drug composition will dependon absorption, inactivation, and excretion rates of the drug as well asother factors known to those of skill in the art. It is to be noted thatdosage values will also vary with the severity of the condition to bealleviated. It is to be further understood that for any particularsubject, specific dosage regimens should be adjusted over time accordingto the individual need and the professional judgment of the personadministering or supervising the administration of the compositions, andthat the dosage ranges set forth herein are exemplary only and are notintended to limit the scope or practice of the claimed composition. Theactive ingredient may be administered at once, or may be divided into anumber of smaller doses to be administered at varying intervals of time.

Combination Treatment

The compound can also be mixed with other active materials which do notimpair the desired action, or with materials that supplement the desiredaction. The active compounds can be administered in conjunction, i.e.combination or alternation, with other medications used in the treatmentor prevention neuropathic pain, stroke, traumatic brain injury,epilepsy, and other neurologic events or neurodegeneration resultingfrom NMDA receptor activation. In another embodiment, the compounds canbe administered in conjunction (combination or alternation) with othermedications used in treatment or prophylaxis of inflammatory conditions.In certain embodiments, the combination can be synergistic although inother embodiments the combination is not synergistic.

Emergency treatment for an ischemic stroke, particularly when the strokeis diagnosed within 3 hours of the start of symptoms, includethrombolytic, or clot-dissolving, medications such as tissue plasminogenactivator (t-PA). Other treatments of an ischemic stroke involveadministering to the patient an antiplatelet medication (aspirin,clopidogrel, dipyridamole), or anticoagulant medication (warfarin),dependent on the cause. Dextrorphan, a pharmacologically activemetabolite of the cough suppressant dextromethorphan, is an NMDAantagonists studied in human stroke patients. Selfotel, a competitiveNMDA antagonist, has also been tested in human patients, however ittrends toward higher mortality within treated patients than withinplacebo-treated cohorts, and therefore, trials were stopped prematurely.A trial of another NMDA receptor antagonist, aptiganel HCl (Cerestat),was terminated. A large, 1367-patient, efficacy trial with the agentGV150526 was completed in 2000.(http://www.emedicine.com/neuro/topic488.htm, Lutsep & Clark“Neuroprotective Agents in Stroke”, Apr. 30, 2004).

EXAMPLES

The following examples are provided to illustrate the present inventionand are not intended to limit the scope thereof. Those skilled in theart will readily understand that known variations of the conditions andprocesses of the following preparative procedures can be used tomanufacture the desired compounds. The materials required for theembodiments and the examples are known in the literature, readilycommercially available, or can be made by known methods from the knownstarting materials by those skilled in the art.

Examples 1 and 2N-(4-{3-[4-(3,4-Difluoro-phenyl)-piperazin-1-yl]-2-(S)-hydroxy-propoxy}-phenyl)-methanesulfonamide(Compound 1) andN-(4-{3-[2-(3,4-Dichloro-phenylamino)-ethylamino-]-2-(S)-hydroxy-propoxy}-phenyl)-methanesulfonamide(Compound 2)

Step (i). 3-(4-Nitro-phenoxy)-2-(S)-propyleneoxide (i-1). 4-Nitrophenol(6.6 mmol) was dissolved in 5 ml anhydrous DMF. Cesium fluoride (19.9mmol) was added to the reaction. The reaction mixture was stirred for 1hour at room temperature and (S)-Glycidyl nosylate (6.6 mmol) was addedto the reaction mixture. The reaction stirred for 24 hours at roomtemperature. Water (150 mL) was added and the solution was extractedwith ethyl acetate. The organic phase was dried over MgSO₄ andevaporated. The residue was purified with column chromatograph usingethylacetate:hexane (50:50) solvent system to give the desired producti-1 This step can be substituted with (R)-Glycidyl nosylate to get the Risomer.

Step (ii). 3-(4-Amino-phenoxy)-2-(S)-propyleneoxide (i-2).(S)-Glycidyl-4-nitrophenyl ether (2.6 mmol, i-1) and 5% Pd/C(en)[{Sajikiet all, Chemistry—a europian journal 6(12):2200-2204 (2000).] (10% ofthe weight of starting material) in 5 ml anhydrous THF was hydrogenatedat ambient pressure and temperature for 3 hours. The reaction mixturewas filtered by using membrane filter (13, 0.22 μm) and the filtrate wasconcentrated in vacuum. The compound was afforded as a crude mixture ofamino reduction compound i-2.

Step (iii). 3-(4-methansulfonylamido-phenoxy)-2-(S)-propyleneoxide(i-3). (S)-Glycidyl-4-aminophenyl ether (2 4 mmol, i-2) dissolved in 20ml anhydrous DCM and N,N-diisopropyl-N-ethylamine (2.6 mmol) was addedat 0° C. After stirring 15 minutes methanesulfonyl chloride (2.6 mmol)was added drop wise to the reaction mixture at 0° C. After stirring overnight, the reaction extracted with water and washed with brine. Organicphase dried over magnesium sulfate and evaporated. The residue waspurified with flash chromatography using Ethyl acetate:DCM (30:70)solvent system to give the desired product i-3.

Step (iv).N-(4-{3-[4-(3,4-Difluoro-phenyl)-piperazin-1-yl]-2-(S)-hydroxy-propoxy}-phenyl)-methanesulfonamide(Compound 1). Compound i-3 (2.00 mmol) andN-(3,4-Difluorophenyl)piperazine (2.00 mmol) were heated under refluxconditions in 20 ml ethanol for 8 hours. Then solvent was evaporated andresidue was purified with flash chromatography usingdichloromethane:methanol (90:10) solvent system to get compound 1.Compound 1 was dissolved in ethanol and bubbled HCl gas to get the HClsalt of the compound 1.

Step (v).N-(4-{3-[2-(3,4-Dichloro-phenylamino)-ethylamino]-2-(S)-hydroxy-propoxy}-phenyl)-methanesulfonamide(Compound 2). The epoxide (i-3, 1.58 mmol) was dissolved in EtOH (20ml), and then the 3,4-dichloro-ethylene diamine (1.58 mmol)(preparation: Isabel Perillo, M. Cristina Caterina, Julieta López,Alejandra Salerno. Synthesis 2004, 6, 851-856) was added and thesolution refluxed for 16 hours. The solvent was evaporated and theproduct purified with column chromatography using 10% MeOH/DCM+1% NH₄OHto give compound 2.

The following compounds were synthesized according to the proceduresprovided in examples 1 and 2.

COMPOUND NAME AND PHYSICAL DATA

N-(4-{3-[4-(3,4-Dichloro-phenyl)-piperazin-1-yl]-2-(S)-hydroxy-propoxy}-phenyl)-methanesulfonamide MS: 475.14486

N-(4-{3-[4-(4-Chloro-phenyl)-piperazin-1-yl]-2-(S)-hydroxy-propoxy}-phenyl)-methanesulfonamide MS: 440.14017

N-(4-{3-[4-phenyl-piperazin-1-yl]-2-(S)-hydroxy-propoxy}-phenyl)-methanesulfonamide MS: 406.20183

N-(4-{3-[4-(4-Hydroxy-phenyl)-piperazin-1-yl]-2-(S)-hydroxy-propoxy}-phenyl)-methanesulfonamide

N-(4-{3-[4-(2-Pyridyl)-piperazin-1-yl]-2-(S)-hydroxy-propoxy}-phenyl)-methanesulfonamide

N-(4-{3-[4-(4-Pyridyl)-piperazin-1-yl]-2-(S)-hydroxy-propoxy}-phenyl)-methanesulfonamide

N-{4-[2-(S)-Hydroxy-3-(2-phenylamino-ethylamino)-propoxy]-phenyl}-methanesulfonamide

N-{4-[2-(S)-Hydroxy-3-(2-(3,4-difluoro-phenyl)amino-ethylamino)-propoxy]-phenyl}- methanesulfonamide MS:416.15842

N-(4-{3-[3-(3,4-Dichloro-phenyl)-allylamino]-2-(S)-hydroxy-propoxy}-phenyl)-methanesulfonamide MS: 446.09479

N-[4-(3-{Butyl-[3-(3,4-dichloro-phenyl)-allyl]-amino}-2-(5)-hydroxy-propoxy)-phenyl]- methanesulfonamide MS: 501.13871

N-(4-{3-[3-(3,4-Difluoro-phenyl)-allylamino]-2-(S)-hydroxy-propoxy}-phenyl)-methanesulfonamide MS: 413.58425

Example 36-{3-[4-(4-Chloro-phenyl)-piperazin-1-yl]-2-(S)-hydroxy-propoxy}-3H-benzooxazol-2-one(Compound 3)

Step (i). 6-(2-(S)-Oxiranylmethoxy)-3H-benzooxazol-2-one (ii-1).5-hydroxy-benzoxazole (310 mg) and cesium carbonate (780 mg) werecombined in 6 mL of N,N-dimethylformamide. The reaction was stirred forroom temperature for 1 hour. (S)-glycidal nosylate (520 mg) was added,and the reaction stirred at room temperature overnight. The reaction wasquenched with NH₄Cl(aq) solution and extracted with ethyl acetate. Theorganic layer was washed with NH₄Cl(aq) and NaCl(aq) solutions,separated, and dried over Na₂SO₄(s). Filtration and solvent removal wasfollowed by absorption onto silica gel. Elution with an ethylacetate/methanol mixture (4:1) followed by solvent removal gave 445 mgof a yellow, oily solid.

Step (ii).6-{3-[4-(4-Chloro-phenyl)-piperazin-1-yl]-2-(S)-hydroxy-propoxy}-3H-benzooxazol-2-one(Compound 3). To a solution of 300 mg of epoxide (ii-1) in 10 mL ofabsolute ethanol was added 300 mg of 4-(4-chlorophenyl)-piperazine. Thesolution was heated to 70° C. for 8 hours. The reaction was cooled andthe solvent removed under vacuum. The residue was purified by columnchromatography on silica gel using ethyl acetate as solvent. Obtained240 mg of a light brown solid (45% yield). 1HNMR (d6-DMSO, 400 MHz): δ2.37 (dq, 2H, J=6 Hz, J=13 Hz), 2.51 (m, 4H), 3.02 (m, 4H), 3.68 (q, 1H,J=8 Hz 3.84 (dd, 1H, J=4 Hz, J=14 Hz), 4.02 (bs, 1H), 5.07 (d, 1H, J=5Hz), 6.61 (dd, 1H, J=2 Hz, J=9 Hz 6.73 (d, 1H, J=2 Hz 6.91 (d, 2H, J=9Hz 7.05 (d, 1H, J=8 Hz 7.21 (d, 2H, J=9 Hz 9.43 (s, 1H); MS (m/z): 404(M+H), 406 (M+2+H); HRMS Calcd. for C20H23ClN3O4: 404.13771. Found:404.13673.

The following compounds were synthesized according to the procedure inExample 3.

COMPOUND NAME AND PHYSICAL DATA

6-{3-[4-(3,4-Dichloro-phenyl)-piperazin-1-yl]-2-(S)-hydroxy-propoxy}-3H-benzooxazol-2-one MS: 406.15664

6-{3-[4-(3,4-Dichloro-phenyl)-piperazin-1-yl]-2-(S)-hydroxy-propoxy}-3H-benzooxazol-2-one

6-{3-[4-(4-Methyl-phenyl)-piperazin-1-yl]-2-(S)-hydroxy-propoxy}-3H-benzooxazol-2-one MS: 384.19077

6-{3-[2-(3,4-Dichloro-phenyl)-ethylamino]-2-(S)-hydroxy-propoxy}-3H-benzooxazol-2-one

6-{3-[2-(4-Chloro-phenylamino)-ethylamino]-2-(S)-hydroxy-propoxy}-3H-benzooxazol-2-one MS: 378.12089

Example 44-{3-[4-(3,4-Dichloro-phenyl)-piperazin-1-yl]-2-(S)-hydroxy-propoxy}-phenol(Compound 4)

Step (i). 3-(4-tert-Butyldimethylsilyloxy-phenoxy)-2-(S)-propyleneoxide(iii-1). 4-(tert-Butyldimethylsiloxy)phenol (1.45 g, 6.25 mmol) in 5 mlanhydrous THF was added dropwise to the suspension of NaH (0.158 g, 6.25mmol) in 5 ml THF. After stirring at room temperature for 2 hoursglycidyl nosylate (1.30 g, 5 mmol) and then 15-crown-5 (25 mol %) wereadded to the reaction mixture. After stirring 24 hours reaction waspoured to ice-water and extracted with ethyl acetate. Organic phase waswashed with water and brine, then dried over sodium sulfate andevaporated. Product was purified by column chromatography usingEtOAc:Hexane (1:9) (yield: 1.06 g 76%). ¹H-NMR (400 MHz, CDCl₃) δ 0.17(6H, s), 0.98 (9H, s), 2.75 (1H, dd, J=2.4, 4.4 Hz), 2.89 (1H, q, J=4.4Hz), 3.33-3.36 (1H, m), 3.90 (1H, dd, J=5.6, 10.8 Hz), 4.16 (1H, dd,J=3.6, 11.2 Hz), 6.69-6.81 (4H, m).

Step (ii).4-{3-[4-(3,4-Dichloro-phenyl)-piperazin-1-yl]-2-(S)-hydroxy-propoxy}-phenoxy-tert-butyldimethylsilane (iii-2). Compound iii-1 (0.280 g, 1 mmol) and1-(4-chlorophenyl)piperazine (0.200 g, 1 mmol) were dissolved in 5 mlEtOH and refluxed for 90 minutes. Solvent was evaporated and thematerial was used in the next step without purification.

Step (iii).4-{3-[4-(3,4-Dichloro-phenyl)-piperazin-1-yl]-2-(S)-hydroxy-propoxy}-phenol(Compound 4). Compound iii-2 was dissolved in 5 ml THF and 2 ml TBAF in1.0M THF solution was added, and stirred for 2 hours. Quenched withammonium chloride solution, extracted with EtOAc. Organic phase wasdried over sodium sulfate and evaporated. Product was purified usingcolumn chromatography using EtOAc:MeOH (95:5). ¹H-NMR (400 MHz, DMSO-d6)δ 2.36-2.61 (6H, m), 3.11 (4H, t, J=4.8 Hz), 3.76 (1H, dd, J=4.0, 6.0Hz), 386 (1H, dd, J=4.4, 10.0 Hz), 3.91-3.95 (1H, m), 4.85 (1H, d, J=4.8Hz), 6.66 (1H, dd, J=2.4, 6.8 Hz), 6.75 (1H, dd, J=2.4, 6.8 Hz), 6.92(1H, dd, J=2.4, 6.8 Hz), 7.21 (1H, dd, J=2.4, 6.8 Hz), 8.90 (1H, s).HRMS: 362.1397 calculated. 362.14696 found.

The following compounds were synthesized according to Example 4.

COMPOUND NAME AND PHYSICAL DATA

4-{3-[4-(3,4-Dichloro-phenyl-piperazin-1-yl]-2-(S)-hydroxy-propoxy}-phenol MS: 397.10811

4-{3-[4-(3,4-Difluoro-phenyl)-piperazin-1-yl]-2-(S)-hydroxy-propoxy}-phenol MS: 365.16672

4-{3-[4-(3,4-Difluoro-phenyl)-piperazin-1-yl]-2-(R)-hydroxy-propoxy}-phenol MS: 365.16657

4-{3-[4-(4-Fluoro-phenyl)-piperazin-1-yl]-2-(S)- hydroxy-propoxy}-phenolMS: 347.17602

4-{3-[4-(3,4-Dimethyl-phenyl)-piperazin-1-yl]-2-(S)-hydroxy-propoxy}-phenol MS: 357.21716

4-{3-[4-(4-Methyl-phenyl)-piperazin-1-yl]-2-(S)- hydroxy-propoxy}-phenolMS: 343.20093

4-{3-[4-(4-Cyano-phenyl)-piperazin-1-yl]-2-(S)- hydroxy-propoxy}-phenolMS: 354.18073

4-{3-[4-(4-Bromo-phenyl)-piperazin-1-yl]-2-(S)- hydroxy-propoxy}-phenolMS: 407.09663

4-{3-[4-(4-Hydroxy-phenyl)-piperazin-1-yl]-2-(S)-hydroxy-propoxy}-phenol MS: 345.18061

4-{3-[4-(4-Methoxy-phenyl)-piperazin-1-yl]-2-(S)-hydroxy-propoxy}-phenol MS: 359.19608

4-{3-[4-(4-Trifluoromethyl-phenyl)-piperazin-1-yl]-2-(S)-hydroxy-propoxy}-phenol MS: 397.17327

4-{3-[4-(4-Biphenyl)-piperazin-1-yl]-2-(S)- hydroxy-propoxy}-phenol MS:405.21643

4-{3-[4-(2,4-Difluoro-phenyl)-piperazin-1-yl]-2-(S)-hydroxy-propoxy}-phenol MS: 365.16651

4-{3-[4-(2-Fluoro-phenyl)-piperazin-1-yl]-2-(S)- hydroxy-propoxy}-phenolMS: 347.17595

4-{3-[4-(2-Chloro-phenyl)-piperazin-1-yl]-2-(S)- hydroxy-propoxy}-phenolMS: 363.14695

4-{3-[4-(2-Chloro-phenyl)-piperazin-1-yl]-2-(S)- hydroxy-propoxy}-phenolMS: 343.20108

4-{3-[4-(2-Cyano-phenyl)-piperazin-1-yl]-2-(S)- hydroxy-propoxy}-phenolMS: 354.18070

4-{3-[4-Phenyl-piperazin-1-yl]-2-(S)-hydroxy- propoxy}-phenol MS:329.18547

4-{3-[4-(3-Fluoro-phenyl)-piperazin-1-yl]-2-(S)- hydroxy-propoxy}-phenolMS: 347.17608

4-{3-[4-(3-Chloro-phenyl)-piperazin-1-yl]-2-(S)- hydroxy-propoxy}-phenolMS: 363.14741

4-{3-[4-(3-Methyl-phenyl)-piperazin-1-yl]-2-(S)- hydroxy-propoxy}-phenolMS: 343.20109

4-{3-[4-(3-Trifluoromethyl-phenyl)-piperazin-1-yl]-2-(S)-hydroxy-propoxy}-phenol MS: 397.17269

4-{3-[2-(3,4-Dichloro-phenyl)-ethylamino]-2-(S)- hydroxy-propoxy}-phenolMS: 357.10159

4-(3-{Butyl-[2-(3,4-dichloro-phenyl)-ethyl]-amino}-2-(S)-hydroxy-propoxy)-phenol MS: 413.12769

4-{3-[2-(3,4-Dichloro-phenyl)-ethylamino]-2-(S)-hydroxy-propoxy}-3-fluoro-phenol MS: 375.03418

4-{3-[2-(3,4-Dichloro-phenyl)-ethylamino]-2-(S)-hydroxy-propoxy}-2-fluoro-phenol MS: 375.03409

1-[2-(S)-Hydroxy-3-(4-hydroxy-phenoxy)-propyl]- 4-phenyl-piperidin-4-olMS: 344.18509

Example 5a(4-{3-[4-(3,4-Difluoro-phenyl)-piperazin-1-yl]-propoxy}-phenyl)-urea(Compound 5)

Step (i). [4-(3-Bromo-propoxy)-phenyl]-carbamic acid tert-butyl ester(iv-1). To a solution of 2.1 g of 4-t-butylcarbonylamino-phenol in 20 mLof acetonitrile was added 3.25 g of cesium carbonate. The reaction wasstirred for one hour, and then 1.5 mL of 1,3-dibromopropane was addedand the reaction stirred for 20 hours. The reaction was then quenchedwith NH₄Cl(aq.) solution. The mixture was extracted with ethyl acetateand washed with NH₄Cl(aq.) and NaCl(aq.) solutions. The organic layerwas separated and dried over Na₂SO₄(s). Filtration and solvent removalgave a light brown oily solid. Hexanes were added and the resultingsolids filtered and washed with Hexanes three times. Drying gave 2.4 gof an off-white solid.

Step (ii).(4-{3-[4-(3,4-Difluoro-phenyl)-piperazin-1-yl]-propoxy}-phenyl)-carbamicacid tert-butyl ester (iv-2). To 305 mg of4-(3,4-Difluoro-phenyl)-piperazine and 335 mg of compound iv-1 was added5 mL of acetonitrile. The reaction was heated to 65° C. overnight. Thereaction was cooled, and then extracted with ethyl acetate. The organiclayers were washed with NaHCO₃(aq.) twice, and the organic layersseparated and dried over Na₂SO₄(s). Filtration and solvent removal gavean light brown solid. Dilution with hexanes, filtration, and washingwith hexanes gave 458 mg of a white solid (iv-2). MS (m/z): 430 (M+H);HRMS: Obsd for C₂₄H₃₃FN₃O₃: 430.24951.

Step (iii). Compound iv-2 (430 mg) was dissolved in 6 mL ofdichloromethane. Next, 4 mL of trifluoroacetic acid was added and thereaction was stirred for 6 hours. Then NaHCO₃(s) was added until thebubbling stopped. Then water was added to the reaction mixture and thereaction was extracted with dichloromethane and washed with NaHCO₃(aq.)twice. The organics were dried over Na₂SO₄(s), and then the solution wasfiltered and the solvent removed under vacuum. The residue was used inthe next step without any purification.

Step (iv).(4-{3-[4-(3,4-Difluoro-phenyl)-piperazin-1-yl]-propoxy}-phenyl)-urea(Compound 5). The aniline from the previous step was dissolved in 10 mLof N,N-dimethyl formamide. Next, 1 mL of trimethylsilyl isocyanate wasadded, and the reaction was stirred at room temperature overnight. Thereaction was then quenched with NaHCO₃(aq.) solution. The reaction wasextracted with ethyl acetate and washed with NaHCO₃(aq.) solution twice.The organic layer was separated and dried over Na₂SO₄(s). Filtration andsolvent removal gave a brown solid. Filtration over a plug of silica gelwith ethyl acetate/methanol (4:1) was followed by solvent removal.Trituration of the resulting solids with ethyl ether and filtration gave98 mg of an off-white solid. MS (m/z): 391 (M+H); HRMS: calcd. forC₂₀H₂₅F₂N₄O₂: 391.19456. Found: 391.19184.

The following compounds were synthesized according to the methods andvariations of described for Example 5.

COMPOUND NAME AND PHYSICAL DATA

(4-{2-[4-(3,4-Difluoro-phenyl)-piperazin-1-ylmethyl]-allyloxy}-phenyl)-urea MS: 403.19326

(4-{3-[4-(4-Fluoro-phenyl)-piperazin-1-yl]- propoxy}-phenyl)-urea MS:373.20319

1-Ethyl-3-(4-{3-[4-(4-fluoro-phenyl)-piperazin-1-yl]-propoxy}-phenyl)-urea

(4-{3-[4-(4-Fluoro-phenyl)-piperazin-1-yl]- propoxy}-phenyl)-carbamicacid methyl ester MS: 388.20251

Example 5b(4-{3-[4-(4-Chloro-phenyl)-piperazin-1-yl]-2-(S)-hydroxy-propoxy}-phenyl)-urea

Step (ii). Epoxide ring opening with p-chlorophenyl-piperazine. To asolution of 1.1 g of p-chloro-phenyl-piperazine in 10 mL of ethanol wasadded 0.95 g of the S-epoxide. The solution was heated for 18 hours at70° C. The reaction was cooled, and extracted with dichloromethane. Theorganic layers were washed twice with NaHCO₃(aq.) solution. The organiclayers were separated, and then dried over Na₂SO₄(s). Filtration andsolvent removal gave an oily residue. Next, ethyl ether was trituratedin and the resulting solids filtered and dried. Obtained 1.49 g ofpiperazine compound as a light yellow solid. ¹H NMR (400 MHz, CDCl₃):2.64 (m, 4H), 2.86 (m, 2H), 3.08 (m, 1H), 3.19 (m, 4H), 4.12 (m, 2H),4.18 (m, 1H), 6.85 (d, 2H, J=8 Hz), 7.01 (d, 2H, J=11 Hz), 8.21 (d, 2H,J=9 Hz); ms (m/z): 392 (M+H). HRMS: m/z 392.13665—theoretical forC₁₉H₂₃O₄N₃Cl—392.13716.

Step (iii). Silyl ether formation p-chlorophenyl-piperazine. To asolution of 1.2 g of alcohol i-2 in dichloromethane was added 600 mg oft-butyldimethylsilyl chloride, 1 mL of diisopropylethyl amine, and 600mg of 4-N,N-dimethylaminopyridine. The reaction was stirred for 1 day,then 150 mg of t-butyldimethylsilyl chloride was added. Stirring for athird day was followed by addition of a third alloquat of 150 mg oft-butyldimethylsilyl chloride. Stirring for an additional day wasfollowed by solvent removal and absorption onto silica gel. The residuewas filtered with a 3:1-Hexane-ethyl acetate mixture and the solvent wasremoved under vacuum. 1.1 g of a yellow, oily solid was obtained. ¹H NMR(CDCl₃): δ 0.08 (s, 3H), 0.11 (s, 3H), 0.88 (s, 9H), 2.52 (m, 2H), 2.65(m, 4H), 3.13 (t, 4H, J=4 Hz), 3.98 (dd, 1H, J=7 Hz, J=9 Hz), 4.16 (m,1H), 4.22 (dd, 1H, J=3 Hz, J=9 Hz), 6.81 (d, 2H, J=9 Hz), 6.96 (d, 2H,J=9 Hz), 7.18 (d, 2H, J=9 Hz), 8.18 (d, 2H, J=9 Hz); MS (m/z): 506(M+H); HRMS: Calcd. for C₂₅H₃₇ClN₃O₄Si: 506.22419. Found: 506.22577.

Step (iv). Nitro group reduction. To a solution of 25 mg of silyl etheri-3 in 6 mL of N,N-dimethylformamide was added 1 g of tin(II)chloridehydrate. The reaction was heated to 65° C. for 20 hours. The reactionwas cooled and quenched by pouring over NaHCO₃(aq.) solution. Themixture bubbled and was allowed to subside. Ethyl acetate was added, andthe materials filtered through celite. The organic layer was extractedwith NaHCO₃(aq.) solution. The aqueous layers were re-extracted withethyl acetate and the organic layers were combined and dried over sodiumsulfate. Filtration, solvent removal, and column chromatography gave 210mg of a clear oil. Repetition with 450 mg of nitro compound i-3 gave 290mg of aniline.

Step (v). Urea formation. To a solution of 500 mg of aniline in 6 mL ofN,N-dimethyl formamide was added 1 mL of trimethylsilyl isocyanate. Thereaction was stirred for 2 days. An additional 0.5 mL of trimethylsilylisocyanate was added and followed by stirring for 2 more days. Thereaction was extracted with ethyl acetate, and washed with NaHCO₃(aq.)solution. The organic layer was separated and dried over Na₂SO₄(s).Filtration, solvent removal, and column chromatography gave 410 mg of awaxy, white solid. ¹H NMR (d⁶-DMSO): δ 0.04 (s, 3H), 0.07 (s, 3H), 0.83(s, 9H), 2.39 (m, 2H), 2.48 (m, 4H), 3.08 (t, 4H, J=4 Hz), 3.75 (dd, 1H,J=7 Hz, J=10 Hz), 3.98 (dd, 1H, J=3 Hz, J=10 Hz), 4.08 (m, 1H), 5.69 (s,2H), 6.76 (d, 2H, J=9 Hz), 6.89 (d, 2H, J=9 Hz), 7.18 (d, 2H, J=9 Hz),7.23 (d, 2H, J=9 Hz), 8.28 (s, 1H).

Step (vi). Desilylation. 400 mg of silyl ether i-5 was dissolved in 10mL of tetrahydrofuran. Next, 2 mL of a tetrabutylammonium fluoridesolution (1M, in THF, Aldrich) was added. The reaction was stirredovernight, and then saturated NH₄Cl(aq.) solution was added. The mixturewas diluted with ethyl acetate, and the resulting solids filtered. Thesolids were washed with water, ethyl acetate, and ethyl ether (threetimes each). Drying gave 220 mg of an off-white powder. ¹H NMR(d⁶-DMSO): 2.42 (m, 2H), 2.54 (m, 4H), 3.08 (t, 4H, J=4 Hz), 3.77 (dd,1H, J=6 Hz, J=9 Hz), 3.89 (m, 2H), 4.85 (d, 1H, J=5 Hz), 5.68 (s, 2H),6.78 (d, 2H, J=9 Hz), 6.89 (d, 2H, J=9 Hz), 7.18 (d, 2H, J=9 Hz), 7.23(d, 2H, J=9 Hz), 8.27 (s, 1H); MS (m/z): 405 (M+H), 407 (M+2+H); HRMS:calcd for C₂₀H₂₆N₄O₃ ³⁵Cl: 405.16934. observed: 405.16872. The p-toluenesulfonate salt was formed by taking 70 mg of the free base and mixing in50 mg of p-toluene sulfonic acid hydrate. The mixture was diluted with 5mL tetrahydrofuran and 3 mL ethanol and heated to 60° C. until allsolids had dissolved. The mixture was cooled, and 90% of the solventremoved under vacuum. Next, ethanol was added and allowed to stand atroom temperature for several hours. The resulting solids were filtered,washed with ethanol three times and dried. Obtained 80 mg of a fluffy,white solid. ¹H NMR (d⁶-DMSO): 2.25 (s, 3H), 2.99 (m, 2H), 3.09 (m, 2H),3.22 (m, 2H), 3.58 (m, 2H), 3.79 (m, 2H), 3.87 (m, 2H), 4.28 (s, 1H),5.74 (s, 2H), 5.97 (s, 1H), 6.81 (d, 2H, J=8 Hz), 6.99 (d, 2H, J=8 Hz),7.08 (d, 2H, J=7 Hz), 7.27 (t, 4H, J=8 Hz), 7.44 (d, 2H, J=8 Hz), 8.36(s, 1H), 9.58 (s, 1H); Anal. Calc. For C₂₀H₂₅N₄O₃C1-pTsOH—H2O: C, 54.49,H, 5.93, N, 9.41. Found: C, 54.82, H, 5.77, N, 9.42.

Example 5c Synthesis of R and S Hydroxy-Propyl Urea Piperazines

Step (i). Preparation of 1-(4-hydroxyphenyl)urea.

To a solution of 10.92 g of 4-hydroxy-aniline in 100 mL oftetrahydrofuran at 65° C. was added 20 mL of trimethylsilyl isocyanate(85%, Aldrich). The solution was heated at 65° C. for 6 hours. Thesolution was cooled to room temperature, and then 100 mL of ethanol and10 g of silica gel were added. The reaction was stirred at roomtemperature overnight. The solvent was removed under vacuum. The solidswere diluted with a 1:1 mixture of dichloromethane and ethanol (500 mL).After all the solids had dissolved, the solution was filtered over aplug of silica gel. The solvent was removed under vacuum. Next,dichloromethane was added and the solids were filtered and washed withdichloromethane three times. The resulting solids were then dried. Thereaction gave 15.5 g of a fine white powder (100% yield). ¹H NMR(d⁶-DMSO): δ 5.62 (s, 2H), 6.58 (d, 2H, J=9 Hz), 7.1 (d, 2H, J=9 Hz),8.12 (s, 1H), 8.91 (s, 1H); MS: 187 (M+Cl); HRMS: 187.02821.

Step (ii). Preparation of(R)-1-(4-(3-chloro-2-hydroxypropoxy)phenyl)urea. (T. Fujioka et al.Chem. Pharm. Bull. 44(8), 1996, 1596-1598.)

To a solution of 1.52 g (10 mmoles) of 1-(4-hydroxyphenyl)urea in 10 mLof methanol and 10 mL of water was added 0.5 mL of triethylamine,followed by 8 mL of (R)-epichlorohydrin. The reaction was homogeneous,and was stirred at room temperature for 20 hours. The reaction wasdiluted with 50 mL of water and extracted with 5×100 mL portions ofethyl acetate. The organics were washed with dilute HCl (aq.) and NaCl(aq.) solutions. The organics were separated and dried over Na₂SO₄(s).Filtration and solvent removal gave an oily residue, which was absorbedonto silica gel. The crude product was then subjected to purification bycolumn chromatography with a gradiant based on a 90:10:1 mixture ofdichloromethane:methanol:NH₄OH and dichloromethane. The fractions ofinterest were combined and the solvent removed under vacuum. Theresulting pink solid was dried under vacuum to give 1.62 g of fluffywhite solid (66% yield). ¹H NMR: (d⁶-DMSO): δ 3.62 (dd, 1H, J=6 Hz, J=11Hz), 3.71 (dd, 1H, J=5 Hz, J=11 Hz), 3.86 (d, 2H, J=5 Hz), 3.96 (m, 1H),5.49 (d, 1H, J=6 Hz), 5.69 (s, 2H), 6.78 (d, 2H, J=9 Hz), 7.24 (d, 2H,J=9 Hz), 8.29 (s, 1H); MS: 279 (M+Cl); HRMS: 279.03124.

Step (iii). Preparation of(5)-1-(4-(3-chloro-2-hydroxypropoxy)phenyl)urea.

Following the exact procedure of the R-enantiomer, 1.52 g (10 mmoles) of1-(4-hydroxyphenyl)urea and 8 mL of (S)-epichlorohydrin gave 1.39 g (57%yield) of light pink solid. The compound had identical ¹HNMR and MSspectra to the (R)-enantiomer.

Step (iv). (S)-1-(4-(oxiran-2-ylmethoxy)phenyl)urea. (T. Fujioka et al.Chem. Pharm. Bull. 44(8), 1996, 1596-1598.) To a solution of 1.62 g ofthe (R)-chlorohydrin (3) in 70 mL of isopropanol and 10 mL of water at0° C. was added a solution of 2 g of KOH dissolved in 12 mL of water.The reaction was stirred for 2 hours at 0° C., during which time a whiteprecipitate formed. After 2.5 hours, 100 mL of ethyl acetate was addedand the reaction was allowed to warm to room temperature. The organiclayer was washed with NaCl (aq.) solution. The aqueous layer wasextracted with 4×100 mL of ethyl acetate, and the organic layers werecombined and dried over Na₂SO₄(s). Filtration and solvent removal gave awhite residue. Ethyl ether was added and the solids were filtered andwashed with ethyl ether three times. Drying gave 1.23 g of a white,fluffy solid (89% yield). ¹H NMR (d⁶-DMSO): δ 2.65 (dd, 1H, J=3 Hz, J=5Hz), 2.79 (t, 1H, J=5 Hz), 3.25 (m, 1H), 3.71 (dd, 1H, J=7 Hz, J=12 Hz),4.2 (dd, 1H, J=3 Hz, J=12 Hz), 5.7 (s, 2H), 6.79 (d, 2H, J=9 Hz), 7.25(d, 2H, J=9 Hz), 8.3 (s, 1H); MS: 243 (M+Cl); HRMS: 243.05458.

Step (v). (R)-1-(4-(oxiran-2-ylmethoxy)phenyl)urea.

Using the same procedure as for the (S)-enantiomer, 1.39 g of theS-chlorohydrin gave 1.11 g (93% yield) of the R-epoxide as a fluffy,white solid. This compound had identical ¹H NMR and MS as theS-enantiomer.

Specific exemplary syntheses for step (vi):

(S)-1-(4-(2-hydroxy-3-(4-phenylpiperazin-1-yl)propoxy)phenyl)urea. Amixture of 0.1 g of (S)-1-(4-(oxiran-2-ylmethoxy)phenyl)urea, 0.14 g ofN-phenyl-piperazine, and 6 mL of absolute ethanol was heated to 70° C.for 20 hrs. The reaction was cooled, and the resulting precipitatecollected by filtration. The solids were washed three times withethanol, and dried. 0.126 g of the title compound was obtained as afluffy white powder was obtained. ¹H NMR (d⁶-DMSO): δ 2.36 (dd, 1H, J=6Hz, J=13 Hz), 2.48 (m, 1H), 2.55 (m, 4H), 3.08 (t, 4H, J=5 Hz), 3.78(dd, 1H, J=6 Hz, J=9 Hz), 3.89 (m, 1H), 3.93 (m, 1H), 4.84 (d, 1H, J=5Hz), 5.68 (s, 2H), 6.73 (t, 1H, J=8 Hz), 6.78 (d, 2H, J=9 Hz), 6.88 (d,2H, J=8 Hz), 7.16 (t, 2H, J=8 Hz), 7.24 (d, 2H, J=9 Hz), 8.27 (s, 1H);MS: 371 (M+H); HRMS: Observed: 371.20723; HPLC: 100% peak areacomposition; retention time=6.64 min.

1-(4-((S)-3-((S)-4-(4-chlorophenyl)-2-methylpiperazin-1-yl)-2-hydroxypropoxy)phenyl)urea.A solution of 0.5 mmol of the (S)-epoxide and 0.6 mmol(35)-1-(4-chlorophenyl)-3-methylpiperazine in 5 ml ethanol was refluxedfor overnight. The solvent was evaporated and product was purified withthe column chromatography using dichloromethane:methanol:NH₄OH(90:10:1). After the column it was crystallized with ethyl acetate togive 0.109 g (52% yield). ¹H NMR (400 MHz, d6-DMSO): δ 1.01 (3H, d,J=6.0 Hz), 2.16 (1H, dd, J=5.6, 12.8 Hz), 2.34-2.51 (3H, m), 2.78-2.89(2H, m), 2.99 (1H, d, J=11.6 Hz), 3.38 (2H, d, J=11.2 Hz), 3.75-3.79(1H, m), 3.88-3.92 (2H, m), 4.84, (1H, d, J=5.2 Hz), 5.67 (2H, s), 6.78(2H, d, J=7.2 Hz), 6.88 (2H, d, J=9.2 Hz), 7.17 (2H, d, J=7.2 Hz), 7.23(2H, d, J=9.2 Hz), 8.25 (1H, s); MS: 419 (M+H); HRMS=419.18431; HPLC=96%peak area at 7.7 min. retention time.

1-(4-((S)-3-((R)-4-(4-chlorophenyl)-2-methylpiperazin-1-yl)-2-hydroxypropoxy)phenyl)urea.A solution of 0.5 mmol of the (S)-epoxide and 0.6 mmol of(3R)-1-(4-chlorophenyl)-3-methylpiperazine in 5 ml ethanol was refluxedovernight. The solvent was evaporated and product was purified with thecolumn chromatography using dichloromethane:methanol:NH₄OH (90:10:1).After the column it was crystallized with ethyl acetate to give 0.099 g(47% yield). ¹H NMR (400 MHz, d⁶-DMSO) δ 1.05 (3H, d, J=6.0 Hz), 2.37(1H, dd, J=4.8, 13.2 Hz), 2.46-2.53 (2H, m), 2.71 (1H, dd, J=6.8, 13.2Hz), 2.78 (1H, t, J=8.8 Hz), 2.95 (1H, d, J=12.0 Hz), 3.40 (2H, d, J=8.8Hz), 3.80-3.83 (1H, m), 3.89, (2H, d, J=6.4 Hz), 4.78 (1H, d, J=4.4 Hz),5.71 (2H, s), 6.82 (2H, d, J=8.8 Hz), 6.91 (2H, d, J=8.8 Hz), 7.20 (2H,d, J=8.8 Hz), 7.27 (2H, d, J=8.8 Hz), 8.29 (1H, s); MS: 419 (M+H);HRMS=419.18437; HPLC=95% peak area at 7.6 min. retention time.

(S)-1-(4-(3-(4-(3,4-difluorophenyl)piperazin-1-yl)-2-hydroxypropoxy)phenyl)urea.A solution of 0.106 g of (S)-epoxide, 0.135 g ofN-(3,4-difluorophenyl)-piperazine and 6 mL of absolute ethanol washeated at 70° C. for 18 hours. The reaction was cooled, and theresulting precipitate filtered. The solids were washed with ethanol andethyl ether three times each. Drying gave 0.12 g of a white solid. ¹HNMR (d⁶-DMSO): 2.36 (dd, 1H, J=7 Hz, J=13 Hz), 2.45 (m, 1H), 2.53 (m,4H), 3.06 (m, 4H), 3.77 (dd, 1H, J=6 Hz, J=9 Hz), 3.88 (m, 1H), 3.91 (m,1H), 4.83 (d, 1H, J=4 Hz), 5.67 (s, 2H), 6.67 (m, 1H), 6.78 (d, 2H, J=9Hz), 6.93 (m, 1H), 7.19 (quart, 1H, J=10 Hz), 7.23 (d, 2H, J=9 Hz), 8.26(s, 1H); MS: 407 (M+H); HRMS: 407.18890; HPLC: 100% peak area at 7.1min. retention time.

(S)-1-(4-(3-(4-(4-fluorophenyl)piperazin-1-yl)-2-hydroxypropoxy)phenyl)urea.A solution of 0.11 g of (S)-epoxide, 0.14 g ofN-(4-fluorophenyl)-piperazine, and 6 mL of ethanol was heated to 70° C.for 20 hours. The solution was cooled to room temperature. The solidswere filtered, washed with ethanol three times, and dried. Gave 0.164 gof a white powder. 1H NMR (d6-DMSO): d 2.36 (dd, 1H, J=6 Hz, J=13 Hz),2.47 (m, 1H), 2.55 (m, 4H), 3.02 (t, 4H, J=5 Hz), 3.77 (dd, 1H, J=6 Hz,J=9 Hz), 3.88 (m, 1H), 3.92 (m, 1H), 4.84 (d, 1H, J=5 Hz), 5.68 (s, 2H),6.78 (d, 2H, J=9 Hz), 6.89 (m, 2H), 6.99 (t, 2H, J=8 Hz), 7.23 (d, 2H,J=9 Hz), 8.27 (s, 1H); MS: 389. (M+H); HRMS: 389.19782; HPLC: 99.2% peakarea at 6.5 min. retention time.

(S)-1-(4-(2-hydroxy-3-(4-(4-methoxyphenyl)piperazin-1-yl)propoxy)phenyl)urea.A solution of 0.11 g of (S)-epoxide, 0.155 g ofN-(4-methoxyphenyl)-piperazine, and 6 mL of ethanol was heated to 70° C.for 20 hours. The solution was cooled to room temperature. The solidswere filtered, washed with ethanol three times, and dried. Gave 0.18 gof a white powder. ¹H NMR (d⁶-DMSO): δ 2.36 (dd, 1H, J=7 Hz, J=13 Hz),2.45 (m, 1H), 2.55 (m, 4H), 2.96 (t, 4H, J=5 Hz), 3.64 (s, 3H), 3.77(dd, 1H, J=6 Hz, J=9 Hz), 3.87 (m, 1H), 3.93 (m, 1H), 4.83 (d, 1H, J=5Hz), 5.68 (s, 2H), 6.78 (m, 4H), 6.83 (d, 2H, J=9 Hz), 7.23 (d, 2H, J=9Hz), 8.27 (s, 1H); MS: 401 (M+H); HRMS: 401.21861; HPLC: 99% peak areaat 6.2 min.

(S)-1-(4-(3-(4-(4-ethylphenyl)piperazin-1-yl)-2-hydroxypropoxy)phenyl)urea.A solution of 0.08 g of (S)-epoxide, 0.12 g ofN-(4-ethylphenyl)-piperazine, and 5 mL of absolute ethanol were heatedat 70° C. for 30 hours. The solution was cooled to room temperature. Thesolvent was removed under vacuum, and the residue subjected to columnchromatography on silica gel with adichloromethane/dichloromethane:methanol:NH₄OH (90:10:1) gradiant.Combination of the fractions and solvent removal, followed by dryingunder vacuum gave 0.064 g of a white solid. ¹H NMR (d⁶-DMSO): δ 1.09 (t,3H, J=8 Hz), 2.36 (dd, 1H, J=6 Hz, J=12 Hz), 2.44 (m, 1H), 2.54 (m, 4H),3.03 (t, 4H, J=5 Hz), 3.77 (dd, 1H, J=6 Hz, J=10 Hz), 3.89 (m, 1H), 3.92(m, 1H), 4.83 (d, 1H, J=5 Hz), 5.67 (s, 2H), 6.78 (d, 2H, J=9 Hz), 6.8(d, 2H, J=8 Hz), 7.01 (d, 2H, J=9 Hz), 7.23 (d, 2H, J=10 Hz), 8.26 (s,1H); MS: 399 (M+H); HRMS: 399.23896; HPLC: 100% peak area; retentiontime at 7.8 min. Elemental—formula+0.25 H₂O—theory: C, 65.57, H, 7.63,N, 13.9. Found: C, 65.58, H, 7.51, N, 13.98.

(S)-1-(4-(3-(4-(4-propylphenyl)piperazin-1-yl)-2-hydroxypropoxy)phenyl)urea.A solution of 0.11 g of (S)-epoxide, 0.154 g ofN-(4-propylphenyl)-piperazine, and 6 mL of ethanol was heated to 70° C.for 20 hours. The solution was cooled to room temperature. The solidswere filtered, washed with ethanol three times, and dried. Gave 0.094 gof a white powder. ¹H NMR (d⁶-DMSO): δ 0.83 (t, 3H, J=7 Hz), 1.49(hextet, 2H, J=7 Hz), 2.38 (m, 3H), 2.54 (m, 4H), 3.03 (t, 4H, J=5 Hz),3.77 (dd, 1H, J=6 Hz, J=9 Hz), 3.89 (m, 1H), 3.92 (m, 1H), 4.83 (d, 1H,J=5 Hz), 5.68 (s, 2H), 6.78 (d, 2H, J=9 Hz), 6.8 (d, 2H, J=8 Hz), 6.98(d, 2H, J=8 Hz), 7.24 (d, 2H, J=9 Hz), 8.27 (s, 1H); MS: 413 (M+H);HRMS: 413.25406; HPLC: 99% peak area at 8.6 min. retention time.

(S)-1-(4-(3-(4-(4-isopropyl-phenyl)piperazin-1-yl)-2-hydroxypropoxy)phenyl)urea.A solution of 0.08 g of (S)-epoxide, 0.16 g ofN-(4-isopropylphenyl)-piperazine, and 5 mL of absolute ethanol wereheated at 70° C. for 30 hours. The solution was cooled to roomtemperature. The solvent was removed under vacuum, and the residuesubjected to column chromatography on silica gel with a dichloromethane:dichloromethane:methanol:NH₄OH (90:10:1) gradient. The fractions werecombined and the solvent removed under vacuum. Ethyl ether was added tothe solids and they were filtered, washed with ethyl ether three times,and then dried. 0.046 g of a white solid was obtained. ¹H NMR (400 MHz,d⁶-DMSO): δ 1.11 (d, 6H, J=7 Hz), 2.36 (dd, 1H, J=7 Hz, J=13 Hz), 2.45(m, 1H), 2.54 (m, 4H), 2.74 (quint, 1H, J=7 Hz), 3.03 (t, 4H, J=5 Hz),3.77 (dd, 1H, J=6 Hz, J=10 Hz), 3.88 (m, 1H), 3.92 (m, 1H), 4.84 (d, 1H,J=5 Hz), 5.68 (s, 2H), 6.8 (t, 4H, J=10 Hz), 7.03 (d, 2H, J=8 Hz), 7.24(d, 2H, J=9 Hz), 8.27 (s, 1H); MS: 413 (M+H); HRMS: 413.25458; HPLC:100% peak area at a retention time of 8.25 min.; Elementalanalysis—Theory: C, 66.96, H, 7.82, N, 13.58. Found, C, 66.98, H, 7.82,N, 13.48.

(S)-1-(4-(3-(4-(4-cyclopropylphenyl)piperazin-1-yl)-2-hydroxypropoxy)phenyl)urea.A solution of 0.1 g of (S)-epoxide, 0.15 g ofN-(4-cyclopropylphenyl)-piperazine, and 6 mL of absolute ethanol wereheated at 70° C. for 20 hours. The solution was cooled to roomtemperature. The solvent was removed under vacuum, and the residuesubjected to column chromatography on silica gel with adichloromethane/dichloromethane: methanol:NH₄OH (90:10:1) gradiant. Thefractions were combined and the solvent removed under vacuum. Ethanolwas added to the solids and they were filtered, washed with ethanolthree times, and then dried. 0.067 g of a white solid was obtained. ¹HNMR: (d⁶-DMSO): δ 0.5 (quart, 2H, J=4 Hz), 0.8 (m, 2H), 1.76 (m, 1H),2.35 (dd, 1H, J=6 Hz, J=12 Hz), 2.46 (m, 1H), 2.54 (m, 4H), 3.01 (t, 4H,J=5 Hz), 3.77 (dd, 1H, J=6 Hz, J=10 Hz), 3.88 (m, 1H), 3.91 (m, 1H),4.83 (d, 1H, J=5 Hz), 5.68 (s, 2H), 6.78 (m, 4H), 6.88 (d, 2H, J=8 Hz),7.23 (d, 2H, J=9 Hz), 8.27 (s, 1H); MS: 411 (M+H); HRMS: 411.23895;HPLC: 100% peak area at 7.8 min. retention time; Elemental analysis:Theory: C, 67.29, H, 7.37, N, 13.65. Found: C, 67.27, H, 7.36, N, 13.54.

(S)-1-(4-(3-(4-(4-isobutylphenyl)piperazin-1-yl)-2-hydroxypropoxy)phenyl)urea

(S)-1-(4-(3-(4-(2-naphthyl)piperazin-1-yl)-2-hydroxypropoxy)phenyl)urea.A solution of 0.11 g of (S)-epoxide, 0.175 g ofN-(2-naphthyl)-piperazine, and 6 mL of ethanol was heated to 70° C. for20 hours. The solution was cooled to room temperature. The solids werefiltered, washed with ethanol three times, and dried. Gave 0.197 g of awhite powder. ¹H NMR (d⁶-DMSO): δ 2.39 (dd, 1H, J=7 Hz, J=12 Hz), 2.49(m, 1H), 2.61 (m, 4H), 3.79 (dd, 1H, J=6 Hz, J=10 Hz), 3.9 (m, 1H), 3.96(m, 1H), 4.86 (d, 1H, J=5 Hz), 5.68 (s, 2H), 6.79 (d, 2H, J=9 Hz), 7.11(d, 1H, J=2 Hz), 7.23 (m, 4H), 7.34 (m, 3H), 7.69 (m, 4H), 8.27 (s, 1H);MS: 421 (M+H); HRMS: 421.22338; HPLC: 99.9% peak area at 7.8 min.retention time.

Specific Exemplary Syntheses for Step (vii):

(R)-1-(4-(3-(4-(4-methylphenyl)piperazin-1-yl)-2-hydroxypropoxy)phenyl)urea.A solution of 0.11 g of (R)-epoxide, 0.13 g ofN-(4-methylphenyl)-piperazine, and 5 mL of absolute ethanol were heatedat 70° C. for 30 hours. The solution was cooled to room temperature. Thesolution was filtered. The solids were washed with ethanol three timesand dried. Gave 0.157 g of a white solid.

(R)-1-(4-(3-(4-(4-ethylphenyl)piperazin-1-yl)-2-hydroxypropoxy)phenyl)urea.A solution of 0.11 g of (S)-epoxide, 0.15 g ofN-(4-ethylphenyl)-piperazine, and 5 mL of absolute ethanol were heatedat 70° C. for 30 hours. The solution was cooled to room temperature. Thesolids were filtered, washed with ethanol and ethyl ether three timeseach. Drying gave 0.1 g of a white solid.

(R)-1-(4-(3-(4-(4-isopropylphenyl)piperazin-1-yl)-2-hydroxypropoxy)phenyl)urea.A solution of 0.11 g of (S)-epoxide, 0.175 g ofN-(4-ethylphenyl)-piperazine, and 5 mL of absolute ethanol were heatedat 70° C. for 30 hours. The solution was cooled to room temperature. Theresulting solids were filtered, washed with ethanol and ethyl etherthree times each. Drying gave 0.094 g of a white solid.

Examples 6, 7, and 8N-[2-(3,4-Dichloro-phenylamino)-ethyl]-3-(4-methanesulfonylamino-phenyl)-propionamide(Compound 6),N-(4-{3-[2-(3,4-Dichloro-phenylamino)-ethylamino]-propyl}-phenyl)-methanesulfonamide(Compound 7), andN-(4-(3-(3-(3,4-dichlorophenyl)-2-oxoimidazolidin-1I)propyl)phenyl)methanesulfonamide(Compound 8)

Step (i) Methyl 3-(4-aminophenyl)propanoate (v-1). Thionyl chloride(14.6 ml, 200 mmol, 3.3 equiv) was added dropwise to a solution of drymethanol (60 ml, 1453 mmol, 24 equiv) at −10° C. After stirring for 10minutes, 3-(4-aminophenyl)propanoic acid (10.0 g, 61 mmol) was added togive a yellow suspension. The solution stirred for 1 hour and was slowlywarmed to room temperature. The resulting solution was concentrated togive a yellow solid. The solid was suspended in ethyl acetate, andNaHCO₃ (aq.) was added until the salt dissolved fully. Solid sodiumbicarbonate was added to give pH 8.The layers were separated and theorganics were washed with brine (aq.). The resulting solution was driedover MgSO₄, filtered, and concentrated to give a yellow solid (10.6 g,98%). ¹H NMR (300 MHz, CDCl₃) 7.00 (d, J=8.3 Hz, 2H), 6.63 (d, J=8.3 Hz,2H), 3.67 (s, 3H), 3.59 (bs, NH₂, 2H), 2.85 (t, J=7.6 Hz, 2H), 2.58 (t,J=8.3 Hz, 2H). ¹³C NMR (300 MHz, CDCl₃) 173.8, 144.9, 130.7, 129.3,115.5, 51.8, 36.4, 30.4. M.S. (ESI) m/z=180.102 (M+H).

Step (ii). Methyl 3-(4-(methylsulfonamido)phenyl)propanoate (v-2). Theester (7.38 g, 41.2 mmol) was dissolved in pyridine (17.0 ml, excess).After cooling to 0° C., methanesulfonyl chloride (4.55 ml, 57.7 mmol,1.4 equiv) was added dropwise. The reaction was warmed to roomtemperature and stirred overnight. The reaction was quenched with waterand diluted with DCM. The layers were separated and the organics werewashed with brine. The resulting solution was concentrated to give a redsolid. The crude material was purified using silica gel chromatography(1 EtOAc/1 Hexanes) to give a white solid (87%). ¹H NMR: (CDCl₃, 400MHz) 7.20 (d, J=8.6 Hz, 2H), 7.15 (d, J=8.6 Hz, 2H), 6.45 (bs, NH, 1H),3.68 (s, 3H), 3.00 (s, 3H), 2.94 (t, J=7.6 Hz, 2H), 2.63 (t, J=7.5 Hz,2H). ¹³C NMR (CDCl₃, 400 MHz): 173.4, 137.6, 135.2, 129.4, 121.4, 51.7,38.5, 35.5, 30.1. M.S. (ESI) m/z=257.56 (M+H)

Step (iii). 3-(4-(methylsulfonamido)phenyl)propanoic acid (v-3). Thesulfonamide ester (1.16 g, 4.5 mmol) was dissolved in methanol (50 ml).To this solution, 1.0 N NaOH (17.0 ml, 17.0 mmol, 3.8 equiv) was added.The mixture was stirred at room temperature overnight. TLC indicated thereaction was finished. The pH of the solution was adjusted to 3 with asolution of aqueous HCl. The volume of methanol was reduced by rotaryevaporation (40 mbar), upon which the product crashed out of solution.The yellow crystals were filtered off and dried (0.900 g, 82%). ¹H NMR(400 MHz, CD₃OD) 7.21 (d, J=8.6 Hz, 2H), 7.17 (d, J=8.6 Hz, 2H), 2.91(s, 3H), 2.89 (t, J=7.6 Hz, 2H), 2.59 (t, J=7.6 Hz, 2H). ¹³C NMR (400MHz, CD₃OD) 176.7, 139.0, 137.7, 130.5, 122.3, 39.1, 36.8, 31.4. M.S.(ESI) m/z=242.05 (M−H).

Step (iv).N-(2-(3,4-dichlorophenylamino)ethyl)-3-(4-(methylsulfonamido)phenyl)propanamideCompound 6). The carboxylic acid (0.700 g, 2.88 mmol) was dissolved inDMF (30.0 ml) and cooled to 0° C. To this solution, DMAP (0.352 g, 2.28mmol, 1.1 equiv), and EDCI (0.552 g, 2.88 mmol, 1.0 equiv) were added togive a clear suspension. After stirring for 30 minutes, the amine (0.590g, 2.88 mmol, 1.0 equiv) in THF (5.0 ml) was added dropwise to give abrown solution. The mixture was warmed to room temperature and stirredovernight. The reaction was monitored by TLC. To quench the reaction, 20mL of 1.0 N HCl was added and the solution was extracted with 3×30 mL ofEtOAc. The orgainic layer was dried with MgSO₄, filtered, andconcentrated to give red oil. The crude material was purified by takingthe residue up in DCM and stirring. Immediately a white powderprecipitated out (0.920 g, 74%). ¹H NMR (400 MHz, CD₃OD) 7.14-7.10(mult, 5H), 6.72 (d, J=2.9 Hz, 1H), 6.51 (dd, J₁=8.9 Hz, J₂=2.6 Hz, 1H),3.27 (t, 2H), 3.10 (t, J=6.4 Hz, 2H), 2.88 (s, 3H), 2.87 (t, J=6.5 Hz,2H), 2.46, (t, J=6.4 Hz, 2H). ¹³C NMR (300 MHz, CDCl₃) 175.8, 150.0,138.7, 138.3, 131.7, 130.5, 122.3, 114.4, 113.6, 44.0, 39.8, 39.2, 39.0,32.3. M.S. Calc'd 429.0681. Found (HRMS) 431.08143 (M+H). E.A. Calc'd:C, 50.24; H, 4.92; N, 9.76. Found: C 49.94, H 4.91, N 9.74.

Step (v).N-(4-(3-(2-(3,4-dichlorophenylamino)ethylamino)propyl)phenyl)methanesulfonamide(Compound 7). The sulfonamide amide ((0.500 g, 1.2 mmol) was dissolvedin THF (30.0 ml). After cooling to 0° C., a solution of Lithium Aluminumhydride (2.0 M solution in THF, 2.3 ml, 4.6 mmol, 4.0 equiv) was addeddropwise. After stirring for 10 minutes at 0° C., the ice bath wasremoved and the reaction mixed was warmed to room temperature andstirred overnight. The mixture was diluted with DCM and water to give anemulsion. Rochelle's salt (sat'd solution) was added and the mixturestirred for 20 minutes before filtering over a pad of celite. Theresulting liquid was separated, and the organics were washed with brine,dried over MgSO₄ and concentrated to give a white foam (0.358 g, 74%).The free base was converted to the HCl salt by bubbling HCl (g) througha solution of substrate dissolved in ethanol. The white powderprecipitated out and was filtered off ¹H NMR (300 MHz, CDCl₃) 7.20-7.11(mult, 5H), 6.69 (d, J=2.8 Hz, 1H), 6.46 (dd, J₁=8.8 Hz, J₂=2.8 Hz),4.36 (bs, 1H, NH), 3.156 (mult, 2H), 3.00 (s, 3H), 2.88 (t, J=6.2 Hz,2H), 2.66 (t, J=7.1 Hz, 4H), 1.86-1.79 (mult, 3H). ¹³C NMR (300 MHz,CDCl₃) 148.1, 139.4, 134.8, 132.8, 130.7, 129.7, 121.6, 119.7, 113.9,112.9, 49.0, 48.2, 43.2, 39.3, 32.9, 31.5. M.S. Calc'd 416.088. Found(HRMS): 416.069.

Step (vi).N-(4-(3-(3-(3,4-dichlorophenyl)-2-oxoimidazolidin-1I)propyl)phenyl)methanesulfonamide(Compound 8). The starting material diamine (0.113 g, 0.27 mmol) wasdissolved in THF (10.0 ml). To this solution 1,1-carbonyldiimidazole(0.048 g, 0.30 mmol, 1.1 equiv) was added. The mixture stirred at roomtemperature overnight. After completion, the solution was evaporated todryness and the residue was taken up in ethyl acetate, washed with brine(1×) and dried over Na₂SO₄, filtered, and concentrated to give a clearoil. The crude material was purified using silica gel chromatography(100% EtOAc) to give a white foam (0.070 g, 58%). ¹H (400 MHz, CDCl₃)7.72 (s, 1H), 7.16 (d, J=8.6 Hz, 2H), 7.07 (d, J=8.6 Hz, 2H), 7.02 (s,1H), 6.64 (d, J=2.9 Hz, 1H), 6.41 (dd, J₁=8.5 Hz, J₂=2.9 Hz), 3.64 (t,J=6.0 Hz, 2H), 3.40-3.36 (mult, 4H), 2.97 (s, 3H), 2.57 (t, J=7.3 Hz,2H), 1.26 (t, J=7.3 Hz, 2H). ¹³C (75 MHz, CDCl₃) 152.6, 147.1, 137.3,136.8, 135.6, 130.9, 129.5, 121.6, 118.0, 113.6, 112.5. M.S. (ESI)Calc'd: 441.0681. Found: 442.07527 (M+H).

Compounds in the following table were synthesized according tovariations in methods described for Examples 6, 7, and 8.

COMPOUND NAME

N-[2-(3,4-Dichloro-phenylamino)-ethyl]-2-(4-methanesulfonylamino-phenoxy)-acetamide

N-(4-{2-[2-(3,4-Dichloro-phenylamino)-ethylamino]-ethoxy}-phenyl)-methanesulfonamide

N-(4-{3-[4-(3,4-Dichloro-phenyl)-piperazin-1-yl]-3-oxo-propyl}-phenyl)-methanesulfonamide

N-(4-{3-[4-(3,4-DiFluoro-phenyl)-piperazin-1-yl]-3-oxo-propyl}-phenyl)-methanesulfonamide

N-(4-{3-[4-(3,4-Dichloro-phenyl)-piperazin-1-yl]-propyl}-phenyl)-methanesulfonamide

N-(4-{2-[4-(3,4-Dichloro-phenyl)-piperazin-1-yl]-2-oxo-ethoxy}-phenyl)-methanesulfonamide

6-{2-[4-(3,4-Dichloro-phenyl)-piperazin-1-yl]-2-oxo-ethoxy}-3H-benzooxazol-2-one

6-{2-[4-(3,4-DiFluoro-phenyl)-piperazin-1-yl]-2-oxo-ethoxy}-3H-benzooxazol-2-one

6-{2-[4-(4-Chloro-phenyl)-piperazin-1-yl]-2-oxo-ethoxy}-3H-benzooxazol-2-one

N-[2-(3,4-Dichloro-phenylamino)-ethyl]-2-(2-oxo-2,3-dihydro-benzooxazol-6-yloxy)-acetamide

N-[3-(3,4-Dichloro-phenyl)-allyl]-2-(4-methanesulfonylamino-phenoxy)-acetamide

N-[2-(3,4-Dichloro-phenylamino)-ethyl]-2-(4- hydroxy-phenoxy)-acetamide

N-[2-(3,4-Dichloro-phenylamino)-ethyl]-3-(4-hydroxy-phenyl)-propionamide

N-[2-(3,4-Dichloro-phenylamino)-ethyl]-2-(3-fluoro-4-hydroxy-phenoxy)-acetamide

Example 9 General synthesis for quinolinone derivatives. Preparation of(S)-6-(3-(4-(4-chlorophenyl)piperazin-1-yl)-2-hydroxypropoxy)-3,4-dihydroquinolin-2(1H)-one

Steps (i) and (ii). Preparation of(S)-6-(oxiran-2-ylmethoxy)-3,4-dihydroquinolin-2(1H)-one. Reactions wereperformed according to the literature (Uno, T. et all; Chem. Pharm.Bull. 43(10) 1724-1733 (1995). Either stereoisomer could be formed from(S) or (R) epichlorohydrin and 6-hydroxy-3,4-dihydroquinolin-2(1H)-one.

Step (iii). A solution of 2 mmol of the quinolinone epoxide and 3 mmol1-(4-chlorophenyl)piperazine in 10 ml ethanol was refluxed overnight.The solid was precipitated during the reflux which was filtered, anddried to give 0.42 g of a white solid (51% yield). ¹H-NMR (400 MHz,CDCl₃) δ 2.55-2.65 (6H, m), 2.81-2.86 (2H, m), 2.93 (2H, t, J=7.6 Hz),2.95-3.23 (4H, m), 3.48 (1H, bs), 3.94-3.99 (2H, m), 4.09-4.15 (1H, m),6.69-6.77 (3H, m), 6.84 (2H, d, J=8.8 Hz), 7.21 (2H, d, J=8.8 Hz), 8.31(1H, s); MS416 (M+H); HRMS416.17306; Elemental Analysis forC₂₂H₂₆ClN₃O₃; Calculated: C, 63.53; H, 6.30; N, 10.10. Found: C, 63.27;H, 6.29; N, 10.05.

Example 10 Preparation of(S)-5-(3-(4-(4-chlorophenyl)piperazin-1-yl)-2-hydroxypropoxy)-1H-benzo[d]imidazol-2(3H)-one

Step (i). A solution of 2-amino-3-nitrophenol (5.08 g, 33 mmol) and(2S)-(+)-glycidyl 3-nitrobenzenesulfonate (8.54 g, 33 mmol) in 75 mL ofacetone was treated with K₂CO₃ (5.00 g, 36.3 mmol) and stirred at refluxfor 18 hours. The suspension was cooled to ambient temperature; thesolids were filtered; and the filtrate concentrated in vacuo to dryness.The resulting solids were partitioned between dichloromethane and water,and the aqueous layer extracted once with DCM. The organic layers werecombined and dried over Na₂SO₄ and concentrated in vacuo to give anorange solid (0.3 g, 86.7% yield). ¹H-NMR (400 MHz, CDCl₃) δ 3.45 (1H,t, J=4.8 Hz), 3.86-4.03 (1H, m), 4.64-4.67 (1H, m), 4.79 (1H, dd, J=2.4,10.8 Hz), 5.14 (1H, t, J=5.6), 7.45 (1H, d, J=9.2 Hz), 7.62 (1H, dd,J=4.8, 9.2 Hz), 8.36 12H, d, J=6.8 Hz).

Step (ii). A solution of 2.54 mmol of(S)-2-nitro-4-(oxiran-2-ylmethoxy)aniline and 3.0 mmol of1-(4-chlorophenyl)piperazine in 10 ml ethanol was refluxed overnight.The solvent was evaporated and product was purified with columnchromatography using DCM:MeOH:NH₄OH (95:5:0.5). Gave 1.033 g (100%yield).

Step (iii).(S)-1-(4-amino-3-nitrophenoxy)-3-(4-(4-chlorophenyl)piperazin-1-yl)propan-2-ol(1.033 g, 2.54 mmol) was suspended in 40 ml ethanol and 30 ml water atroom temperature and treated with excesses of sodium bicarbonate (2.56g, 30.48 mmol) and sodium hydrosulfite (6.24 g, 30.48 mmol). The orangereaction mixture slowly became colorless in 3-4 hours, and the mixturewas left to stir at room temperature for overnight. The suspension wasfiltered, and the filtrate concentrated in vacuo to a leave a whitesolid. This residue was partitioned between DCM and water, and theorganic layer washed two times with brine. The combined organic extractswere concentrated in vacuo to give light brown solid (0.43 g, 45%yield). The compound was used directly for the next step without furtherpurification.

Step (iv). The compound from step iii (0.430 g, 1.14 mmol) was suspendedin mixture of 8 ml toluene and 14.25 ml 2N HCl at room temperature withvigorous stirring. An excess of triphosgene (3.61 g, 11.93 mmol) wasadded, and the stirring continued for overnight. The biphasic mixturewas cautiously quenched and neutralized with sodium bicarbonate, causingan pinkish-white precipitate to form at the interface. The precipitatewas filtered and purified with column chromatography usingDCM:MeOH:NH₄OH (90:10:1) to give 0.283 g of a brown solid (47% yield).¹H-NMR (400 MHz, d₆-DMSO): δ 2.32-2.45 (1H, m), 2.53-2.64 (4H, m), 3.11(4H, t, J=5.2 Hz), 3.79-3.83 (1H, m), 3.91 (1H, dd, J=4.0, 9.6 Hz),3.94-4.01 (1H, m), 4.89 (1H, d, J=4.4 Hz), 6.51 (1H, d, J=2.4 Hz), 6.54(1H, s), 6.79 (1H, d, J=8.4 Hz), 6.93 (2H, d, J=9.6 Hz), 7.22 (2H, d,J=9.2 Hz), 10.39 (1H, s), 10.52 (1H, s); HRMS=403.15259; HPLC=2.804retention time (99% purity); Elemental analysis for C₂₀H₂₃ClN₄O₃ x 0.75mol H2O: Calculated: C, 57.69; H, 5.93; N, 13.46. Found: C, 57.63; H,5.63; N, 13.45.

Example 11 Preparation of(S)-6-(3-(4-(4-chlorophenyl)piperazin-1-yl)-2-hydroxypropoxy)quinolin-2(1H)-one

Steps i and ii. Steps i and ii: Preparation of(S)-6-(oxiran-2-ylmethoxy)-quinolin-2(1H)-one. Reactions were performedaccording to the literature (Uno, T. et all; Chem. Pharm. Bull. 43(10)1724-1733 (1995). Either stereoisomer could be formed from (S) or (R)epichlorohydrin and 6-hydroxy-3,4-dihydroquinolin-2(1H)-one.

Step (iii). A solution of 2 mmol the (5)-dihydroquinolinone epoxide and3 mmol 1-(4-chlorophenyl)piperazine in 10 ml ethanol was refluxedovernight. The solid was precipitated during the reflux which wasfiltered, washed with ethanol, and dried to give 0.314 g of a whitesolid (76% yield). ¹H-NMR (400 MHz, dmso-d₆) δ 2.42 (1H, dd, J=6.4, 12.8Hz), 2.53-2.64 (4H, m), 3.11 (4H, t, J=5.2 Hz), 3.88-3.92 (1H, m), 4.00(2H, d, J=6.4 Hz), 4.94 (1H, d, J=4.4 Hz), 6.48 (1H, d, J=9.6 Hz), 6.92(2H, d, J=9.2 Hz), 7.15-7.25 (5H, m), 7.83 (1H, d, J=9.6 Hz), 11.64 (1H,s); HRMS=414.15720; HPLC=8.196 retention time (99% purity); Elementalanalysis: C₂₂H₂₄ClN₃O₃; Calculated: C, 63.84; H, 5.84; N, 10.15. Found:C, 63.42; H, 5.80; N, 10.11.

Example 12 Preparation of(S)-5-(3-(4-(4-chlorophenyl)piperazin-1-yl)-2-hydroxypropoxy)indolin-2-one

Step (i). Diethylazodicarboxylate (40% solution in toluene, 1.9 mL, 4.4mmol) was added to a mixture of 5-hydroxyoxindole (0.65 g, 4.4 mmol),triphenylphosphine (1.14 g, 4.4 mmol), and (S)-glycidol (0.29 mL, 4.4mmol) in anhydrous tetrahydrofuran at 0° C. After the addition, themixture was stirred at 20° C. for 16 h. The volatiles were evaporated ona rotavap and the residue was purified on silica gel using hexane/ethylacetate solvent mixture. Yield: 0.4 g (impure). ¹H NMR (400 MHz, CDCl₃):δ 8.29 (b.s, 1H), 6.92 (s, 1H), 6.78 (s, 2H), 4.22 (m, 1H), 3.88 (m,1H), 3.52 (s, 2H), 3.36 (m, 1H), 2.91 (m, 1H), 2.76 (m, 1H).

Step (ii). A mixture of (S)-indolinone epoxide (0.35 g, 1.7 mmol) and4-chlorophenylpiperazine (0.35 g, 1.8 mmol) in ethanol (10 mL) washeated at 70° C. for 16 hours. The reaction mixture was cooled to roomtemperature and volatiles were evaporated. The residue was purified onsilica gel using a dichloromethane:methanol:ammonia solvent mixture.Gave 0.17 g (25%) of a brown solid. ¹H NMR (400 MHz, d⁶-DMSO): δ 10.19(b.s), 7.21 (d, 2H), 6.92 (d, 2H), 6.88 (s, 1H), 6.77 (d, 1H), 6.68 (d,1H), 4.88 (d, 1H), 3.96 (m, 1H), 3.91 (m, 1H), 3.80 (m, 1H), 3.43 (s,2H), 3.11 (m, 4H), 2.58 (m, 4H), 2.41 (m, 1H). ES-MS m/z 402.16(C₂M₂₄ClN₃O₃+1)⁺. Analysis Calculated for C₂₁H₂₄ClN₃O₃: % C, 62.76; % H6.02; % N 10.46. found: % C, 62.62; % H, 6.06; % N, 10.36.

Example 13 Preparation of(R)-6-(3-(5,6-dichloro-1H-benzo[d]imidazol-2-ylthio)-2-hydroxypropoxy)benzo[d]oxazol-2(3H)-one

Step i. (S)-6-(oxiran-2-ylmethoxy)benzo[d]oxazol-2(3H)-one. A mixture of0.6 g of 6-hydroxy-2-benzoxazolinone and 0.75 g of potassium carbonatewas diluted with 8 mL of N,N-dimethylformamide. The reaction was stirredat room temperature for 1 hour, and then 1.2 g of (S)-glycidyl nosylatewas added. The reaction was stirred for 3 days at room temperature. Thereaction was then quenched with water, extracted with NaHCO₃(aq.)solution and ethyl acetate. The organic layer was separated and driedover Na₂SO₄(s). Filtration and solvent removal gave a residue that wassubjected to column chromatography (hexanes-ethyl acetate gradient).Fraction combination and solvent removal gave 0.39 g of a white solid(47% yield). ¹H NMR (d⁶-DMSO): δ 2.6 (quart, 1H, J=3 Hz), 2.76 (t, 1H,J=4 Hz), 3.23 (m, 1H), 3.71 (dd, 1H, J=6 Hz, J=15 Hz), 4.11 (dd, 1H, J=3Hz, J=15 Hz), 6.59 (dd, 1H, J=2 Hz, J=9 Hz), 6.73 (d, 1H, J=2 Hz), 7.06(d, 1H, J=8 Hz), 9.48 (s, 1H).

Step (ii). Preparation of(R)-6-(3-(5,6-dichloro-1H-benzo[d]imidazol-2-ylthio)-2-hydroxypropoxy)benzo[d]oxazol-2(3H)-one.5,6-Dichloro-2-thiabenzimidazole. ¹H NMR (d6-DMSO): δ 3.59 (dd, 1H, J=6Hz, J=8 Hz), 3.7 (d, 2H, J=6 Hz), 3.93 (t, 1H, J=25 Hz), 4.93 (M, 2h),6.17 (dd, 1H, J=2 Hz, J=8 Hz), 6.3 (d, 1H, J=3 Hz), 6.94 (d, 1H, J=8Hz), 7.7 (s, 2H), 9.4 (s, 1H), 9.59 (s, 1H), 12.98 (s, 1H); MS (m/z):426 (M+H), 428 (M+2+H); HRMS: Calcd. for C₁₇H₁₄ ³⁵Cl₂N₃O₄5: 426.00821.Found: 426.00739.

The following compounds were prepared using similar procedures.

(R)-1-(4-(3-(5,6-dichloro-1H-benzo[d]imidazol-2-ylthio)-2-hydroxypropoxy)phenyl)urea.To a solution of 0.19 g of 5,6-dichloro-1H-benzo[d]imidazole-2-thiol in4 mL of N,N-dimethylformamide was added 0.36 g of cesium carbonate. Thereaction was stirred at room temperature for 2 hours. Next, 0.1 g of the(S)-epoxide was added, and the reaction heated to 60° C. for 18 hours.The reaction was cooled, extracted with ethyl acetate and washed withNaHCO₃ (aq.) solution. The aqueous layer was re-extracted with ethylacetate, and the organic layers combined and dried over Na₂SO₄(s).Filtration and solvent removal gave a dark yellow solid. Columnchromatography with an ethyl acetate/methanol gradient gave an off-whitesolid after fraction combination and solvent removal. The solids wereheated with ethyl acetate to 70° C. for 15 minutes. The solution wascooled, filtered, and the solids were washed with ethyl acetate. Dryinggave 0.099 g of a white solid. ¹H NMR (d⁶-DMSO): δ 3.31 (bs, 1H), 3.38(dd, 1H, J=7 Hz, J=13 Hz), 3.55 (dd, 1H, J=5 Hz, J=13 Hz), 3.91 (m, 2H),4.09 (m, 1H), 5.68 (s, 2H), 6.79 (d, 2H, J=9 Hz), 7.24 (d, 2H, J=9 Hz),7.64 (s, 2H), 8.27 (s, 1H); MS: 429 (M+H+2), 427 (M+H); HRMS: 427.03926;HPLC: 100% peak area at 7.1 min. retention time.

(R)—N-(4-(3-(5,6-dichloro-1H-benzo[d]imidazol-2-ylthio)-2-hydroxypropoxy)phenyl)methanesulfonamide.Physical data: ¹H NMR (d⁶-DMSO): δ 2.84 (s, 3H), 3.99 (dd, 1H, J=7 Hz,J=13 Hz), 3.56 (dd, 1H, J=5 Hz, J=14 Hz), 3.96 (m, 2H), 4.12 (m, 1H),6.9 (d, 2H, J=9 Hz), 7.1 (d, 2H, J=9 Hz), 7.65 (s, 2H), 9.38 (bs, 1H);MS: 462 (M+H), 464 (M+2+H); FIRMS: calcd. for C₁₂H₁₈ ³⁵Cl₂N₃O₄S₂:462.01158. Observed: 462.01045.

(R)—N-(4-(2-hydroxy-3-(6-methyl-1H-benzo[d]imidazol-2-ylthio)propoxy)phenyl)methanesulfonamide.A solution of 0.25 g of 6-methyl-1H-benzo[d]imidazol-2-thiol and 0.5 gof cesium carbonate in 5 mL of N,N-dimethylformamide was stirred at roomtemperature for one hour. Next, 0.25 g of the sulfonamide (S) epoxidewas added and the reaction was heated to 60° C. for 8 hours. Thereaction was cooled, and diluted with water. The aqueous phase wasextracted with ethyl acetate, and Physical data: ¹H NMR (d⁶-DMSO): δ2.34 (s, 3H), 2.84 (s, 3H), 3.36 (dd, 1H, J=8 Hz, J=13 Hz), 3.5 (dd, 1H,J=5 Hz, J=13 Hz), 3.95 (m, 2H), 4.1 (quint, 1H, J=6 Hz), 5.7 (bs, 1H),6.89 (d, 2H, J=9 Hz), 6.9 (m, 1H), 7.1 (d, 2H, J=9 Hz), 7.17 (bs, 1H),7.26 (d, 1H, J=6 Hz), 9.39 (bs, 1H); MS m/z: 408 (M+H); HRMS: Calcd. forC₁₈H₂₂N₃O₄S₂: 408.10517. Found: 408.10416.

Compound Name

(R)-4-(3-(5,6-dichloro-1H-benzo[d]imidazol-2-ylthio)-2-hydroxypropoxy)phenol

(R)-5-(3-(5,6-dichloro-1H-benzo[d]imidazol-2-ylthio)-2-hydroxypropoxy)indolin-2-one

(R)-6-(3-(5,6-dichloro-1H-benzo[d]imidazol-2-ylthio)-2-hydroxypropoxy)-3,4- dihydroquinolin-2(1H)-one

(R)-6-(3-(5,6-dichloro-1H-benzo[d]imidazol-2-ylthio)-2-hydroxypropoxy)quinolin-2(1H)- one

Example 14 Expression of Glutamate Receptors in Xenopus laevis Oocytes

cRNA was synthesized from linearized template cDNA for rat glutamatereceptor subunits according to manufacturer specifications (Ambion).Quality of synthesized cRNA was assessed by gel electrophoresis, andquantity was estimated by spectroscopy and gel electrophoresis. Stage Vand VI oocytes were surgically removed from the ovaries of large,well-fed and healthy Xenopus laevis anesthetized with 3-amino-benzoicacid ethyl ester (3 gm/l) as previously described. Clusters of isolatedoocytes were incubated with 292 U/ml Worthington (Freehold, N.J.) typeIV collagenase or 1.3 mg/ml collagenase (Life Technologies,Gaithersburg, Md.; 17018-029) for 2 hr in Ca²⁺-free solution comprisedof (in mM) 115 NaCl, 2.5 KCl, and 10 HEPES, pH 7.5, with slow agitationto remove the follicular cell layer. Oocytes were then washedextensively in the same solution supplemented with 1.8 mM CaCl₂ andmaintained in Barth's solution comprised of (in mM): 88 NaCl, 1 KCl, 2.4NaHCO₃, 10 HEPES, 0.82 MgSO₄, 0.33 Ca(NO₃)₂, and 0.91 CaCl₂ andsupplemented with 100 μg/ml gentamycin, 10 μg/ml streptomycin, and 10μg/ml penicillin. Oocytes were manually defolliculated and injectedwithin 24 hrs of isolation with 3-5 ng of NR1 subunit cRNA and 7-10 ngof NR2 cRNA subunit in a 50 nl volume, or 5-10 ng of AMPA or kainatereceptor cRNAs in a 50 nl volume, and incubated in Barth's solution at18° C. for 1-7 d. Glass injection pipettes had tip sizes ranging from10-20 microns, and were backfilled with mineral oil.

Example 15 Two Electrode Voltage Clamp Recording from Xenopus laevisOocytes

Two electrode voltage-clamp recordings were made 2-7 days post-injectionas previously described. Oocytes were placed in a dual-track plexiglassrecording chamber with a single perfusion line that splits in aY-configuration to perfuse two oocytes. Dual recordings were made atroom temperature (23° C.) using two Warner OC725B two-electrode voltageclamp amplifiers, arranged as recommended by the manufacturer. Glassmicroelectrodes (1-10 Megaohms) were filled with 300 mM KCl (voltageelectrode) or 3 M KCl (current electrode). The bath clamps communicatedacross silver chloride wires placed into each side of the recordingchamber, both of which were assumed to be at a reference potential of 0mV. Oocytes were perfused with a solution comprised of (in mM) 90 NaCl,1 KCl, 10 HEPES, and 0.5 BaCl₂; pH was adjusted by addition of 1-3 MNaOH of HCl. Oocytes were recorded under voltage clamp at −40 mV. Finalconcentrations for control application of glutamate (50 μM) plus glycine(30 μM) were achieved by adding appropriate volumes from 100 and 30 mMstock solutions, respectively. In addition, 10 μM final EDTA wasobtained by adding a 1:1000 dilution of 10 mM EDTA, in order to chelatecontaminant divalent ions such as Zn²⁺. Concentration-response curvesfor experimental compounds were obtained by applying in successivefashion maximal glutamate/glycine, followed by glutamate/glycine plusvariable concentrations of experimental compounds. Dose response curvesconsisting of 4 to 8 concentrations were obtained in this manner. Thebaseline leak current at −40 mV was measured before and after recording,and the full recording linearly corrected for any change in leakcurrent. Oocytes with glutamate-evoked responses smaller than 50 nA werenot included in the analysis. The level of inhibition by appliedexperimental compounds was expressed as a percent of the initialglutamate response, and averaged together across oocytes from a singlefrog. Each experiment consisted of recordings from 3 to 10 oocytesobtained from a single frog. Results from 3-6 experiments were pooled,and the average percent responses at antagonist concentrations werefitted by the equation,

Percent Response=(100−minimum)/(1+([conc]/IC₅₀)^(nH))+minimum

where minimum is the residual percent response in saturatingconcentration of the experimental compounds, IC₅₀ is the concentrationof antagonist that causes half of the achievable inhibition, and nH is aslope factor describing steepness of the inhibition curve. Minimum wasconstrained to be greater than or equal to 0.

TABLE A ASSAY RESULTS FOR COMPOUNDS PREPARED IN EXAMPLES 1 AND 2.COMPOUND IC₅₀ at pH 6.9 (nM) IC₅₀ at pH 7.6 (nM)

31 557

12 62

296 1,020

32 270

213 1,020

2,400 28,000

1,810 12,700

>30,000 >30,000

55 133

108 199

7 38

163 2,580

38 71

TABLE B ASSAY RESULTS FOR COMPOUNDS PREPARED IN EXAMPLE 3. COMPOUND IC₅₀at pH 6.9 (nM) IC₅₀ at pH 7.6 (nM)

79 726

145 1,700

185 1,500

72 644

185 446

25 97

TABLE C ASSAY RESULTS FOR COMPOUNDS PREPARED ACCORDING TO EXAMPLE 4.COMPOUND IC₅₀ at pH 6.9 (nM) IC₅₀ at pH 7.6 (nM)

80 814

131 611

87 980

50 272

87 529

1,500 5,790

70 260

460 4,370

73 204

576 4,700

562 9,740

113 448

6,950 191,300

529 3,560

541 1,730

978 4,390

430 3,930

3,210 8,330

217 476

211 598

257 4,800

341 1,740

386 3,790

197 501

585 6,500

116 330

114 549

191 298

TABLE D ASSAY RESULTS FOR COMPOUNDS MADE ACCORDING TO EXAMPLE 5.COMPOUND IC₅₀ at pH 6.9 IC₅₀ at pH 7.6

82 696

557 10,400

117 625

46 452

19 60

3,030 15,700

1,540 16,200

TABLE E ASSAY RESULTS FOR COMPOUNDS MADE ACCORDING TO EXAMPLES 6, 7, AND8. COMPOUND IC₅₀ at pH 6.9 IC₅₀ at pH 7.6

30 55

2 21

160 809

13 58

14 36

670 5,330

2,200 8,400

230 2,730

40 129

41 45

307 467

189 243

80 150

10 70

280 515

210 339

Example 16 In Vitro Binding Studies for Secondary Effects

Compounds were evaluated for binding to the human ether-a-go-gopotassium channel (hERG) expressed in HEK293 cells by displacement of³[H]-astemizole according to the methods by Finlayson et al. (K.Finlayson., L. Turnbull, C. T. January, J. Sharkey, J. S. Kelly;[3H]Dofetilide binding to HERG transfected membranes: a potential highthroughput preclinical screen. Eur. J. Pharmacol. 2001, 430, 147-148).Compounds were incubated at 1 or 10 μM final concentration, induplicate, and the amount of displaced ³[H]-astemizole determined byliquid scintillation spectroscopy. In some cases, a seven concentration(each concentration in duplicate) displacement curve was generated todetermine an IC₅₀.

Binding to the rat alpha-1 adrenergic receptor in rat brain membraneswas determined by displacement of ³[H]-prazosin (P. Greengrass and R.Bremner; Binding characteristics of 3H-prazosin to rat braina-adrenergic receptors. Eur. J. Pharmacol. 1979, 55: 323-326). Compoundswere incubated at 0.3 or 3 μM final concentration, in duplicate, and theamount of displaced ³[H]-prazosin determined by liquid scintillationspectroscopy.

Binding IC₅₀ values were determined from displacement curves (four-sixconcentrations, each concentration in duplicate) fit by a non-linear,least squares, regression analysis using MathIQ (ID Business SolutionsLtd., UK). The binding Ki's were determined from the IC₅₀ according tothe method of Cheng and Prusoff (Y. Cheng and W. H. Prusoff;Relationship between the inhibition constant (K1) and the concentrationof inhibitor which causes 50 percent inhibition (IC50) of an enzymaticreaction. Biochem. Pharmacol. 1973, 22: 3099-3108).

TABLE F COMPARISON OF IC50 VALUES FOR NMDA ANTAGONISM AT PH 6.9 AND 7.6AND HERG AND A1 ADRENERGIC RECEPTORS IC₅₀ pH hERG α1 6.9 IC₅₀ pH Ki IC₅₀Compound (nM) 7.6 (nM) (nM) (nM)

74 555 39,000 720

51 447 1,600 620

32 270 553 350

46 452 13,000 340

410 3,830 ~1,000 ~300

69 550 ~7,500 ~350

14 103 ~7,500 ~350

>10,000 >10,000 — —

370 29 ~10,000 ~100

16 76 ~7,500 ~150

12 66 ~5,000 ~100

Example 17 Metabolic Stability

Compounds were incubated with pooled human (from at least 10 donors) orrat liver microsomes, 1.0 mg/ml microsomal protein, and 1 mM NADPH, inbuffer at 37 C. in a shaking water bath according to the method ofClarke and Jeffrey (S. E. Clarke and P. Jeffrey; Utility of metabolicstability screening: comparison of in vitro and in vivo clearance.Xenobiotica 2001. 31: 591-598). At 60 min the samples were extracted andanalyzed for the presence of the parent compound by LC-MS/MS. The parentmaterial remaining in the sample at 60 min is compared to that at 0 minand expressed as a percentage. A control compound, testosterone, was runin parallel.

Example 18 Plasma Half-Life and Brain Exposure

Rats (n=3 per dose) were administered compounds at a doses of 1-4 mg/kgin a single bolus i.v. infusion (2 ml/kg body weight) via the tail veinformulated in 2% dimethyl acetamide/98% 2-hydroxy-propyl cyclodextrin(5%). Animals were fasted overnight prior to dose administration andfood returned to the animals two hours after dosing. Following IVdosing, blood samples (ca 200 μL) were collected into separate tubescontaining anticoagulant (K-EDTA) via the orbital plexus at varioustimes post administration. Plasma samples were prepared immediatelyafter collection by centrifugation for ten minutes using a tabletopcentrifuge, and stored at −80° C. Brain tissue was weighed, homogenizedon ice in 50 mM phosphate buffer (2 ml per brain) and the homogenatestored at −80° C. Plasma and brain homogenate samples were extracted bythe addition of 5 volumes of cold acetonitrile, mixed well by vortexingand centrifuged at 4000 rpm for 15 minutes. The supernatant fractionswere analyzed by LC-MS/MS operating in multiple reaction monitoring mode(MRM). The amount of parent compound in each sample was calculated bycomparing the response of the analyte in the sample to that of astandard curve.

TABLE G PLASMA STABILITY RESULTS PK- AUC (0-last i.v. i.v. h) i.v. t½Cmax XMPK Formu- Compound (hr) ng/ml (hr * ng/mL) Dosing lation

2.7 252 1031* (a) 1 MPK, 0-4 hr i.v.; 2% DMA/98% 2-HPBCD (5% in Water)

2.4 241 452 (b) 1 MPK, 0-6 hr i.v.; 5% DMA/95% 2-HPBCD (5% in Water)

2.6 1069 2351 (b) 3 MPK, 0-4 hr i.v.; 2% DMA/98% 2-HPBCD (5% in Water)

>2 i.p.** 13403 (30 m), 13057 (2 hr), 60 MPK, i.p. NP/ Ricerca 5%DMA/95% 2-HPBCD (5% in Water)

0.8 464 347 (b) 1 MPK, 0-6 hr i.v.; 5% DMA/95% 2-HPBCD (5% in Water)

0.6 193 187 (a) 1 MPK, 0-4 hr i.v.; 2% DMA/98% 2-HPBCD (5% in Water)

0.6 288 217 (a) 1 MPK, 0-4 hr i.v.; 2% DMA/98% 2-HPBCD (5% in Water)

0.6 568 364 (a) 1 MPK, 0-4 hr i.v.; 2% DMA/98% 2-HPBCD (5% in Water)

1.14 715 787.4 (b) 1 MPK, 0-6 hr i.v.; 5 MPK, 0-6 hr 10% DMA/10%EtOH/30% 2- HPBCD/ 50% water

≦0.8 hr 377 (30 m) 3 MPK i.v. (Ricerca) 2% DMA/98% 2-HPBCD (5% in Water)

1.84 575.7 1096 (b) 1 MPK, 0-6 hr i.v.; 5 MPK, 0-6 hr 10% DMA/10%EtOH/30% 2- HPBCD/ 50% water

~0.83 i.p. 960 (15 m) 10 MPK i.p., (NeurOp/ Yerkes) 50% DMSO/50% saline

≦0.8 hr 398 (30 m) 3 MPK i.v. (Ricerca) 2% DMA/98% 2-HPBCD (5% in Water)

~0.5 hr 413 (30 m) 3 MPK i.v. (Ricerca) 2% DMA/98% 2-HPBCD (5% in Water)

TABLE H BRAIN PENETRATION RATIO: Brain:plasma BBB Pene Compound (Direct)Dosing Formulation Classification

10.2 (avg); 11 (30 m), 9.5 (1 hr), 3 MPK i.v. 2% DMA/98% 2-HPBCD (5% inWater) High

2.3 (avg); 2.3 (30 m), 2.9 (1 hr), 1.7 (2 hr) 3 MPK i.v. (Ricerca) 2%DMA/98% 2-HPBCD (5% in Water) Moderate

0.77 (avg); 0.7 (30 m), 0.7 (2 hr), 0.9 (4 hr) 60 MPK i.p. NP/Ricerca 5%DMA/95% 2-HPBCD (5% in Water) Moderate

0.42 (avg); 0.24 (30 m), 0.53 (1 hr), 0.49 (6 hr) 3 MPK i.v. @ 6 hr, 1MPK @ 0.5 hr and 2 hr (Ricerca) 2% DMA/98% 2-HPBCD (5% in Water) Low

0.59 (avg); 0.68 (30 m), 0.49 (1 hr), 3 MPK i.v. (Ricerca) 2% DMA/98%2-HPBCD (5% in Water) High

Below Detection limit (~0) 1 MPK i.v.; (Absorption) 10% DMA/10% EtOH/30%2- HPBCD/50% water Low

0.33 (avg); 0.25 (15 m), 0.49 (30 m), 0.30 (1 hr), 0.36 (2 hr) 10 MPKi.p., (NeurOp/ Yerkes) 50% DMSO/50% saline Moderate \

0.07 (avg.); 0.04 (15 m), 0.06 (30 m), 0.07 (1 hr), 0.10 (3 hr) 1 MPKi.v.; (Absorption) 10% DMA/10% EtOH/30% 2- HPBCD/50% water Moderate

0.25 (avg); 0.15 (30 m), 0.35 (1 hr), BLQ (2 hr) 3 MPK i.v. (Ricerca) 2%DMA/98% 2-HPBCD (5% in Water) High

BLQ (avg); BLQ (30 m), BLQ (1 hr), 3 MPK i.v. (Ricerca) 2% DMA/98%2-HPBCD (5% in Water) Moderate

TABLE I ORAL ABSORPTION AUC (0-last % Ab- p.o. p.o. h) p.o. sorbed p.o.Tmax t½ (hr * ng/ Dos- Formu- Compound (% F) Cmax hr hr mL) ing lation

145.7** 1556.6 2.67 6.46 8451 10 MPK, 0-8 hr p.o. 2% DMA/ 98% 2-HPBCD(5% in Water)

82.2 558 0.5 3.04 1856 5 MPK, 0-6 hr p.o. 5% DMA/ 95% 2-HPBCD (5% inWater)

31.6 407 0.33 0.85 549 5 MPK, 0-6 hr p.o. 5% DMA/ 95% 2-HPBCD (5% inWater)

7.9** 57.8 6.7 nc 284 10 MPK, 0-8 hr p.o. 2% DMA/ 98% 2-HPBCD (5% inWater)

6.2** 30.6 8 nc 132 10 MPK, 0-8 hr p.o. 2% DMA/ 98% 2-HPBCD (5% inWater)

3.3** 10.2 5.3 nc 56.4 10 MPK, 0-8 hr p.o. 2% DMA/ 98% 2-HPBCD (5% inWater)

1-11. (canceled)
 12. A method of treatment or prophylaxis of neuropathicpain, stroke, traumatic brain injury, epilepsy, and other neurologicevents or neurodegeneration resulting from NMDA receptor activationcomprising administering to a host in need thereof an effective amountof a compound of Formula I, or a pharmaceutically acceptable salt,ester, prodrug or derivative thereof:

wherein: each L is independently C₁-C₆ alkyl, C₁-C₆ alkoxy,C(═O)—(C₁-C₆)-alkyl, C₁-C₆ haloalkyl, alkaryl, hydroxy, —O-alkyl,—O-aryl, —SH, —S-alkyl, —S-aryl, fluoro, chloro, bromo, iodo, nitro, orcyano; or two L groups may be taken together with Ar¹ to form: adioxolane ring or a cyclobutane ring; k=0, 1, 2, 3, 4 or 5; each Ar¹ andAr² is independently aryl or heteroaryl; W is a bond, C₁-C₄ alkyl, orC₂-C₄ alkenyl; X is a bond, NR¹ or O; each R¹ and R² is independently H,C₁-C₆ alkyl, C₂-C₆ alkenyl or C₆-C₁₂ aralkyl; or R¹ and R² can be takentogether to form a 5-8 membered ring; each R³ and R⁴ is independently H,C₁-C₆ alkyl, C₁-C₆ alkoxy, C(═O)—(C₁-C₆)-alkyl, C₁-C₆ haloalkyl,hydroxy, fluoro, chloro, bromo, iodo, nitro, or cyano; or CR³R⁴ is C═O;n=1, 2, 3 or 4; p=2, 3, or 4; each R⁵ and R⁶ is independently H, C₁-C₆alkyl, C₁-C₆ alkoxy, C(═O)—(C₁-C₆)-alkyl, C₁-C₆ haloalkyl, hydroxy,fluoro, chloro, bromo, iodo, nitro, or cyano; or CR⁵R⁶ is C═O or C═CH₂;or wherein —NR²— (CR⁵R⁶)— can be

Y is a bond, O, S, SO, SO₂ CH₂, NH, N(C₁-C₆ alkyl), or NHC(═O); Z is OH,NR⁶R⁷, NR⁸SO₂(C₁-C₆ alkyl), NR⁸C(O)NR⁶R⁷, NR⁸C(S)NR⁶R⁷, NR⁸C(O)O(C₁-C₆alkyl), NR⁸-dihydrothiazole, or NR⁸-dihydroimidazole; wherein each R⁶,R⁷ and R⁸ is independently H, C₁-C₆ alkyl or C₆-C₁₂ aralkyl; or

wherein R⁹ and R¹⁰ are each independently H, C₁-C₆ alkyl, aralkyl;wherein when X is a bond, Y is O and Ar² is phenyl, Z is notNR⁸SO₂(C₁-C₆ alkyl); and when X is O, —NR²—(CR⁵R⁶)_(p)— is not—NH—C(═O)—, optionally in a pharmaceutically acceptable carrier.
 13. Themethod of claim 12, wherein the administration is for treatment of ahost suffering from neuropathic pain.
 14. The method of claim 12,wherein the administration is for reducing neuronal injury in a hostsuffering from a stroke or a traumatic brain injury. 15-26. (canceled)27. A method of treatment or prophylaxis of neuropathic pain, stroke,traumatic brain injury, epilepsy, and other neurologic events orneurodegeneration resulting from NMDA receptor activation comprisingadministering to a host in need thereof an effective amount of acompound of Formula V or a pharmaceutically acceptable salt, ester,prodrug or derivative thereof:Ar′—W′—B′—W″—Y′—Ar″—Z′  Formula V wherein B′ is selected from the groupconsisting of:

W′ is a bond or C₁-C₄ alkyl; W″ is C₁-C₄ alkyl, C₁-C₄ hydroxyalkyl,C₁-C₄ haloalkyl or C(═O)—C₁-C₄ alkyl; Y′ is selected from a bond, O, S,CH₂ and N; Ar′ is a substituted or unsubstituted aromatic or nonaromaticcycloalkyl which optionally may include 0-3 heteroatoms; Ar″ is anaromatic or nonaromatic cycloalkyl which optionally may include 0-3heteroatoms; Z′ is NRC(O)NR₂; wherein each R is independently selectedfrom H, C₁-C₆ alkyl or C₆-C₁₂ aralkyl; or Ar″—Z′ are taken together andselected from the group consisting

optionally in a pharmaceutically acceptable carrier.
 28. The method ofclaim 12, wherein X is NR¹.
 29. The method of claim 28, wherein R¹ andR² are taken together to form a 5-8 membered ring so that—NR¹—(CR³R⁴)_(n)—NR²— is


30. The method of claim 29, wherein


31. The method of claim 12, wherein —NR²—(CR⁵R⁶)_(p)— is


32. The method of claim 12, wherein W is a bond.
 33. The method of claim12, wherein Y is O.
 34. The method of claim 12, wherein Z isNR⁸C(O)NR⁶R⁷.
 35. The method of claim 12, wherein


36. The method of claim 12, wherein the compound is presentsubstantially in the form of a single enantiomer.
 37. The method ofclaim 27, wherein B′ is


38. The method of claim 27, wherein W″ is —CH₂ or CH(OH)—CH₂—.
 39. Themethod of claim 27, wherein Ar″ is phenyl.
 40. The method of claim 27,wherein Z′ is NRC(O)NR₂.
 41. The method of claim 27, wherein Z and Ar″are taken together and selected from the group consisting of:


42. The method of claim 27, wherein Ar′ is substituted with (L′)_(k)′and each L′ is independently C₁-C₆ alkyl, C₁-C₆ alkoxy,C(═O)—(C₁-C₆)-alkyl, C₁-C₆ haloalkyl, alkaryl, hydroxy, —O-alkyl,—O-aryl, —SH, —S-alkyl, —S-aryl, fluoro, chloro, bromo, iodo, nitro, orcyano; or two L′ groups may be taken together with Ar′ to form: adioxolane ring or a cyclobutane ring; and k′=0, 1, 2, 3, 4 or
 5. 43. Themethod of claim 42, wherein an L′ group is in the para position on Ar′.44. The method of claim 43, wherein L′ in the para position is ahalogen.
 45. The method of claim 43, wherein L′ in the para position isa C₁-C₆ alkyl.
 46. The method of claim 27, wherein the compound isselected from the group consisting of: